Sophia doesn't see the Winchesters again until shortly after the episode "Are You There God? It's Me, Dean Winchester" when she arrives in response to a call she received from Bobby Singer, whom Ellen had introduced her to previously. The Winchesters are suspicious that despite being a hunter, Sophia was not visited by the ghosts. Something Sophia later attributes to her having spent so many years blocking out the spirits. It is in the episode, "Metamorphosis", that Ruby reveals to Sam who Sophia is and tells him that Mammon, "has his army of demons out hunting that little bitch down. If they get her than Mammon's gonna make Azazel look like puppy." Sam attempts to contact Sophia after this without the knowledge of Dean but is unable to track her down.
When Dean runs across Sophia while they are both working the same hunt and sees her using her demonic abilities, he mistakenly believes that she has been possessed by a demon and stabs her with the demon killing blade. When this has no effect he still thinks she must be some other supernatural creature and attempts to shoot her. It is only through Sam's intervention that Dean does not kill her and the brothers rush her to Bobby's who manages to save her life. Despite Sophia's pleading Sam tells Dean all about who Sophia is (at least as much as Ruby has told him). The Winchester's and Bobby are then called away by Castiel and Sophia runs, not wanting Dean to change his mind and kill her.
Sophia does not run across the Winchesters again for many months, though at one point Castiel informs Sam that she is attempting to help protect the seals in exchange for information. Before Castiel, hunters only believed Angels to be a bedtime story to make up for all the horrors they see, which is why before then, Sophia never suspected that Mammon would be a fallen angel. She had found it odd that unlike other demons, Mammon could not possess her body with her consent, but as Angels were unknown, she had spent almost two decades believing him to be a demon. Instead, Mammon was an angel who followed Lucifer after he was expelled from heaven and offered a place in hell, with an army of demons at his command. But because he would be made mortal if he were to leave hell and reach Earth as punishment for his turning away from heaven, it was only through a host that he could walk the Earth but still retail his abilities.
The next time Sophia meets the Winchesters is in the episode, "When the Levee Breaks". After being attacked by demons and badly injured, Sophia goes to Bobby for help as he is the only hunter in the area. While there she learns of Sam's Demon Blood addiction. Sophia's presence unnerves Castiel as he calls her "an abomination" on several occasions. When she goes down to see Sam, only to see him knocking out Bobby. In her wounded state Sam is able to overpower her by knocking her unconscious. Sam hallucinates that Sophia is telling him to drink her blood but manages to ignore the hallucination, steal a car, and escape. By the time she comes to, Bobby informs her of all she's missed: that Sam is going to kill Lilith, that in order to do so he must ingest enough demon blood to make himself something less than human, and of the falling out between the Winchester boys. Sophia agrees to help Dean stop Lucifer from getting free of his cage.
In "Lucifer Rising" Sophia is mostly healed, something that unsettles both Dean and Bobby, and preparing to help Dean in any way she can from Lucifer being unleashed. However both Bobby and Sophia are shocked when Dean disappears, something they later learn was the work of Zachariah. Demons attack and in the process Bobby is possessed and forced to go after the Winchesters, while Sophia is knocked unconscious and dragged to hell by the demons. She awakens later to discover that she is trapped in hell and Mammon plans to torture her until she finally gives into his demands and allows him to inhabit her body.