Like Dean, Sam calls Castiel by the nickname Dean gave him, "Cas".
Castiel and Sam don't meet for awhile, but they are both aware of each other's existence. Sam hears about Castiel from Dean. Castiel knew about Sam, and the fact that Sam was using his powers to exorcise demons with his mind. Sam does want to meet Castiel, mainly because he wants to thank the angel who dragged his brother out of hell. The two do finally meet face to face in Its the Great Pumpkin, Sam Winchester.
- "Sam Winchester. The boy with the demon blood. Glad to hear you’ve… ceased your extracurricular activities."
- —Castiel to Sam[src]
Then the angels reveal they plan to destroy the town, and Sam (as well as Dean) doesn't like this plan at all. Sam tries to talk the angels out of it by saying they can stop the witch before she summons a very powerful Demon. Castiel tells Sam and Dean they have their orders. Sam asks them if angels are supposed to show mercy.They meet again in Heaven and Hell, when Castiel comes for Anna. Sam asks Castiel why they would want to kill an innocent girl. Castiel responds by saying that Anna is far from innocent. Sam is confused by this. Uriel attacks when they continue refusing to give Anna to the angels. Sam asks Castiel to stop this, but Castiel merely knocks Sam out with a touch and heads to where Anna is. Then, Castiel and Uriel are sent away by Anna. Because of what Castiel tells Sam, Sam starts to investigate Anna.
After saving Castiel in On The Head Of A Pin, Castiel comes to Dean's hospital, where Sam is sitting beside his brother's bedside. Sam demands Castiel gets in there and heal Dean. Castiel tells Sam he can't. Sam argues that Cas and Uriel are the ones who put Dean in there, all because they can't keep a simple devil's trap together. Castiel apologizes to Sam, unable to explain what happened. Sam snaps at Castiel, saying that making Dean torture again was for nothing. It's not the demons, but something else. Castiel brings up the possibility that Alastair was lying, but Sam shoots it down. Castiel believes Sam is right about this.
They don't see each other after that. Although in When the Levee Breaks, it is Castiel who lets Sam out of the panic room. Castiel also aids Dean to get to Sam, so Dean can stop the breaking of the final seal.
- "The answer is still no, because Sam is my friend."
In I Believe The Children Are Our Future, Castiel shoots downs Sam's plan to talk to Jesse about what's happening to him. Sam argues that once Jesse knows the truth, he will stop hurting people. Castiel points out that Sam didn't, and leaves. This comments hurts Sam (due to his guilt about drinking demon blood).When Sam figures something is not right in a town, he calls Castiel in for help (99 Problems). When Castiel shows up drunk, he tells Sam he finds his voice grating. Sam notices Castiel is drunk and asks what happened to Cas. Castiel answers he found a liquor store and "drank it". Sam attempts to help Castiel from wobbling, and asks if he's okay. Castiel leans over and tells Sam not to ask stupid questions. Sam tells Castiel about the demon attacks around town and the "prophet" Leah Giden. Castiel tells Sam that she is no prophet (because all the names of the prophets are seared into Cas's brain), and then Sam asks then what Leah is. Castiel later reveal that "Leah" is actually the Whore of Babylon. When Cas brings a weapon to kill her, he tells them that only a true servant of God can use it to kill her. Castiel continues on by saying he can't do it, and, neither can Sam since he's an abomination (because of the demon blood). Sam looks slightly hurt, but understands.
When Dean decides to say 'yes' to Michael in Point of No Return, Sam brings Castiel along to help him stop Dean. Castiel uses his powers to send Dean to Bobby's house. Like Sam, Castiel is angry at Dean for giving up, so they both work together to make sure Dean doesn't leave Bobby's. When Dean does escape, Castiel brings Dean back unconcious. Sam asks Castiel what happened and Castiel answers "Me". Later on, Sam decides to bring Dean along on a mission, despite Castiel not wanting to Dean to come along. Castiel can't understand Sam's blind faith in Dean.
As the final showdown comes along, Castiel comes once again to aid the Winchesters. In Two Minutes to Midnight, Castiel saves Sam from being strangled to death. Castiel is amazed how useful guns can be. Then in Swan Song, Castiel says an awkward goodbye to Sam, as Sam prepares to have an internal battle with Lucifer in his head.
After Sam returned from hell, he called Castiel many times, but Castiel never answered, so Sam stopped calling. In The Third Man Sam tells Dean that Castiel won't answer, but when Dean calls Cas, he appears, which surprises Sam, who mocks Castiel's "Hello". Sam continues by saying that he's been calling Castiel all this time and Cas only comes when Dean calls him. Sam continues by asking if Castiel likes Dean more. Castiel answers by saying he and Dean share a more profound bond. Castiel also tells Sam he has no idea who brought Sam back from the cage, or why. When Sam tries to get more information, Castiel angrily replies "What part of I don't know escapes your understanding?" Later on in a fight with another angel, Castiel destroys Sam's car.In Family Matters, Castiel is trying to figure out what is wrong with Sam. Castiel starts asking Sam questions, and finishes with asking how Sam feels emotionally. Sam answers he doesn't know. Castiel tries to feel Sam's soul, only to find out Sam doesn't have one. Sam looks shocked at this discovery. Castiel tells Dean whoever brought Sam back, left his soul behind. When Dean asks if "Sam" is still even Sam, Castiel answers that it is an interesting philosophical question.
Castiel continues to help in the quest for Sam's soul in Caged Heat. Although he doesn't come right away. Sam tricks Castiel into coming down and calls Castiel an idiot for believing his lie. Sam asks Castiel to help, but Castiel refuses (due to the civil war). Sam continues by saying Cas owes him and if Castiel doesn't help, Sam will find a way to kill Castiel (pointing out the extra time to do so since Soulless Sam doesn't sleep). So Castiel agrees to help. Later on, Castiel seemingly threatens Crowley to get Sam's soul back, but when Crowley says he can't, Castiel toasts Crowley's bones. Castiel reassures Sam they will find another way to get Sam's soul back.In Like A Virgin, Sam now has his soul and Dean calls Castiel to check on Sam. Castiel tells Dean that Sam's soul felt like it had been skinned alive. Later on in the episode, Sam calls Castiel. Castiel tells Sam its good to see him alive and attempts to hug Sam (who sits down to avoid it). Sam tells Castiel he would hug Castiel, but it would be awkward. Sam goes on to talk about how its been a crazy year and how he just talked to Bobby about it. Castiel tells Sam he's surprised Sam even survived. Castiel asks Sam how it feels. Sam looks confused. Castiel explains, "to have your soul back". Sam is shocked to hear this news and plays along so he can get more details from Castiel about what really happened.
After hunting Eve down, Sam (plus Bobby) begin to have suspicions about Castiel. Sam starts not to trust Castiel, and believes him to be working with Crowley (The Man Who Would Be King). Castiel still protects Sam and Dean despite these doubts. Then when Castiel's betrayal comes to light, they trap Cas in a ring of holy fire. In there, Castiel reveals he was the one who brought Sam back. Sam asks Castiel if he meant to bring Sam back soulless. Castiel tells Sam he didn't mean to (he didn't even know until Family Matters).Despite Castiel's betrayal, Sam wants to call and does call Castiel for help in Let It Bleed. Although Cas doesn't show himself, he answers Sam's prayer. Then Castiel does the unthinkable in The Man Who Knew Too Much. In order to detour Dean, he breaks down the wall inside Sam's mind and Sam goes into a coma. Castiel says he'll save Sam, only if they back off. Sam does wake from his coma, and comes to Dean's rescue. Sam stabs Castiel only to find out that Angel Blade doesn't work on him.
- "Dean, look, I know you think that Cas is gone" "Cause he is" "He's not. He's in there somewhere, Dean. I know it""
- —Sam and Dean about Castiel[src]
Even after Castiel tore down his wall, Sam still believes that they can reach him. Despite Dean thinking Cas won't listen, Sam calls Castiel, and tells him they can help. Although Castiel doesn't answer right away, he comes to Sam's call and asks for help. Sam sets out with the others to help Castiel.
The last moment they have together is when Castiel tells Sam where to find the blood cocktail meant to open Purgatory. Later, Castiel is overcome by the Leviathans, and Sam watches Castiel disappear into the water.
In The Born-Again Identity, Castiel comes to Sam's rescue as a demon attempts to fry Sam's brain. Castiel attempts to right his wrong by attempting to fix Sam's mental state, but fails. Castiel deeply regrets what he did to Sam, and he states that he can't fix it. Then the idea hits Castiel to switch places with Sam's mental state. Castiel takes on Sam's insanity, and begins to see Lucifer. Now sane, Sam is shocked to see Castiel alive, and becomes worried about how he's acting. Sam is a bit shocked that Dean wants to leave Castiel in the mental institution.
In Reading Is Fundamental, Sam thanks Castiel for what helping him and taking on his hell. Sam promises to help find a cure for what Castiel took on. Castiel tells Sam that Sam doesn't need to fix anything and that taking on Sam's pain gave him purpose. Castiel also mentions that he doesn't see Lucifer anymore since it was Sam's own hallucination. Sam is sadden to hear Castiel doesn't think that he's broken.
Sam inquired about what happened to Castiel in Purgatory, but got no answer from Dean. Sam is excited to see Castiel's return and is less suspicious of it than Dean.Hunteri Heroici, Sam and Castiel make a connection when Sam is talking about living in a dream. When Castiel brings himself and Sam into the mind of Fred Jones, Castiel can relate to Sam, as he too, has been running from his problems, and makes a decision to return to Heaven, but is shot down by Naomi.
In Clip Show, when Castiel's relationship with Dean is strained due to Dean's anger over Castiel's lack of trust in him, Sam comforts Castiel, trying to convince him that Dean just needs time.
In "I Think I'm Gonna Like It Here," Castiel agrees to stop helping Hael in order to come and save Sam when he's dying. He also gives Dean his approval of Ezekiel helping, saying Ezekiel is a good soldier and indicating they are friends.
In "I'm No Angel," When Castiel is being tortured by the Reaper possessing April Kelly, Sam comes to his rescue with Dean though Castiel is briefly killed. Afterwards, Castiel is excited by the idea of Sam and Dean being his guides to being human, but Dean is forced to ask him to leave to save Sam who "Ezekiel" threatens to leave and let die if Castiel doesn't go.
In "Holy Terror," Castiel works a case of angel deaths with Sam and Dean, but "Ezekiel" once again forces Dean to send him away. However, this time, Dean partially explains why to Castiel who continues investigating on his own. After learning from Malachi that Ezekiel is dead, Castiel escapes and calls Dean to warn him that the angel who helped Sam isn't really Ezekiel. Unfortunately, his warning comes too late.
In "Road Trip", after the angel possessing Sam kills Kevin and takes off, Castiel comes to aid Dean with saving him. While Dean is originally going to kill Sam to kill the angel, Castiel presents the solution of going to Crowley for help to get him to do what he did with Samandriel to bring out Sam and get him to expel the angel. After finding "Sam", Castiel knocks him out and watches as Crowley tortures the angel to get information, admitting to Dean that its not easy for him to watch. He is also able to confirm that the angel did in fact heal most of the damage to Sam's body from the Trials. Castiel is furious to learn that the angel is actually Gadreel, the angel that allowed evil into the Garden of Eden and thus started all of the chaos on Earth. Dean eventually asks Castiel to possess Sam to help him force Gadreel out, but Castiel can't do that as he needs Sam's permission. However, Crowley can so at Dean's request, Castiel removes Sam's Devil's Trap Tattoo so Crowley can possess him. While waiting to see if it will work, Castiel reassures Dean. Finally, with Crowley's help, Sam expels Gadreel and Castiel heals the wounds he got from the torture, promising to finish Gadreel's healing of him though it will take time. When Dean leaves, Castiel stays with Sam.
In "First Born," Castiel stays with Sam in the bunker, trying to enjoy human things such as a sandwich but having a hard time as an angel. He also pushes him to make up with Dean. Castiel has nearly finished healing Sam and when he goes to give him his next treatment, he discovers that Sam still has some of Gadreel's grace inside him. Castiel discovers that they can use the residual grace to track Gadreel from the Men of Letters files and painfully starts extracting the grace from Sam. Castiel soon discovers that losing the grace is causing Sam to start to revert back to the state he was in before Gadreel possessed him, but Sam insists they keep going as he wants to make up for his past which Castiel reluctantly agrees to. Eventually Sam's condition deteriorates badly and Castiel chooses to finish healing him completely, destroying the rest of the grace rather than sacrifice Sam even though they might not have enough grace for the spell. Castiel explains that being human has taught him that he was wrong in the past about doing whatever it takes to achieve what he wants and that he empathizes with Sam as he is the only one who has screwed up more times than Sam has. With this, Castiel officially loses any remaining disgust he holds towards Sam and his nature. After the spell fails, an appreciative Sam gives a stunned Castiel a hug and he eventually returns it.