Samantha arrives at Charles University and she reveals that she can not afford a meal plan. She meets her new love interest, Devon Sylver, and just as things start to look good for Samantha, it all comes crashing down when something tragic happens. Meanwhile, actress Dawn Vargas arrives at Charles University in search for a normal life but she gets drunk at the local University hotspot, a club named Colony, and Trent, the bartender, decides to help her.
After Samantha complains to Darryl about the noise from her roommate, Kathryn, in her dorm room, Darryl imposes an eviction bylaw to anyone who makes excessive noise in the dormitory. The other dormitory students blame Samantha for the bylaw despite her protest that she did not mean for this to happen. In hopes of winning back the hearts of the students in the dormitory, Samantha decides to break the rules and plan a party. Meanwhile, Kathryn decides to plan her own party.
Samantha attends the club fair with her new friend Dawn and quickly decides she wants to join a sorority. However, there is only one spot available and her competition becomes Kathryn. Kathryn, knowing that Samantha has a better chance of getting in the exclusive sorority than she does, decides to dig up some dirt on Samantha's life. While at Colony, Sam finds Kathryn making out with Beau, the boyfriend of the sorority's leader, Sloane. After Sloane confronts Sam about the dirt dug up by Kathryn, Sam decides to tells Sloane about Kathryn and Beau. However, Sloane is not impressed by Samantha's intentions. Meanwhile, Sam and Devon's relationship begins to blossom, but it does not last long.
Samantha and Noah's business teacher gives them a huge assignment and the students with the lowest marks from the assignment will be forced to drop the course due to over enrollment. Sam and Noah decide to partner up for their business assignment, only to learn they must sell calendars plastered with pictures of Devon. With Devon and Sam's relationship still on the rocks, Sam builds up the courage to ask Devon for help.
Samantha and Devon get back together and when all the pieces seem all to fall in place, a new problem ensues. Devon and Sam decide to go to the Halloween party at Colony dressed as ketchup and mustard. Everything is fine before Cynthia shows up drunk and dressed as relish. Sam becomes torn between spending time with her new boyfriend or Cynthia. When Sam finally confronts Cynthia, she does something shocking.
Samantha becomes stressed over her upcoming exams and temporarily moves in with Dorothy to get some quiet study time. Sam visits Cynthia in the hospital and is determined to find out what is wrong with her. Meanwhile, Dawn's diva attitude causes the entire cast and crew of "Macbeth" to quit and Sam discovers Cynthia's secret.
Sam's birthday is coming up and Devon decides to make it the best birthday that Sam has ever had. But the festive mood is put to a halt when a person from Sam's past makes an unwelcomed appearance.
Devon and Sam's relationship has become serious and Devon tells Sam that he loves her but Sam doesn't know how to respond. Sam tries to mend the relationship between Dawn and Trent, but the circumstance proves to be much more difficult than she first anticipated when Trent makes his feelings clear to Sam.
Sam tries to deal with the aftermath of kissing Trent and she decides that she cannot trust him. She tries avoiding Trent but it proves difficult when Sam has to see him at work. Meanwhile Colony gets robbed and Sam and Trent are locked in the backroom. And Devon's jealousy issues get the best of him and leaves Sam a message on her phone that he later regrets.
Devon tries to talk to Sam about what he did but she refuses to talk him. Sam is determined to let her hair down and empower herself but ends up landing herself in jail. Patrick reveals to Sam that she is adopted.
Trent asks his father to help Sam find her biological parents. Despite his disapproval, Trent agrees to have dinner with Sam and his parents at his parent's house. Meanwhile, Professor Fisher discovers who ruined his marriage.
Patrick returns and Sam learns that Dorothy isn't as honorable as everyone thinks. Dawn realizes Devon is still in love with Sam and Beau assaults Kathryn.
Sam finally meets her birth mother, but her isn't so exited. Also, her relationship with Trent starts growing, which freaks him out. Devon is offered to play in Italy. Kathryn considers dating Noah. Later, after Alana sends the stripping video to her parents, her dad tells her she has to leave college. Dawn plans a road trip to L.A. before they start shooting the movie. After the director says it's not possible, she starts having cold feet about it.
After heading to South America for eight months, Samantha Best returns to Charles University to find that things have changed. Trent, Dawn and Devon have all left C.U., but that doesn't mean that Sam won't make new friends. New students Delman, Robyn, Rich, Poppi and Jake all arrive and shake things up. Meanwhile, Noah must sort out his feelings for Kathryn after her return.
Noah films a documentary for his film class on a subject very dear to him- Robyn. Unfortunately, she doesn't seem to have enough time to give him a proper interview. This leads to Noah filming Kat and jealousy sparks. Meanwhile, Sam is failing out of her literature class and Dorothy steps in. Not knowing what exactly to do with her life, she parallels her life to her literature assignment.
After receiving an assignment in class, Sam sets up a play about her thoughts and emotions to show to the students of C.U. Meanwhile, Del and Kat form an unlikely friendship when they begin picking apart their choice of friends. Robyn, exhausted from all of her medical school duties, decides to act out as well.
Samantha has her work cut out for her when Alicia's antics go too far. Not only does her latest stunt make a mockery of Dorothy, but it might cost Samantha her place at C.U. Meanwhile, a bad boy named Jake arrives and stirs up trouble for everyone.
The gang at the dorm gathers together when Samantha hosts a Canadian Thanksgiving for Noah. However, Samantha and Rich's relationship unravels. Meanwhile, Del learns that he and his family no longer have any money.
Sam assists Poppi in distributing condoms on campus, and Sam is surprised to find herself bonding with Jake, Alicia's ex.
After hearing details about her aunt's romantic history, Sam contemplates giving Rich a second chance.
In the second-season finale, Sam and her pals commit to doing something that requires facing their fears and achieving happiness.