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.

In the second-season finale, Sam and her pals commit to doing something that requires facing their fears and achieving happiness.