It's been several years since a magical pair of jeans -- that somehow managed to fit all four girls and their distinct body types perfectly -- helped best friends Tabitha "Tibby" Tomko-Rollins (AMBER TAMBLYN), Bridget Vreeland (BLAKE LIVELY), Lena Kaligaris (ALEXIS BLEDEL) and Carmen Lowell (AMERICA FERRERA) get through some tough times in their lives as they spent the summer apart.
It's now that same time of year but after their first year of college, and once again the girls have gone their separate ways. Tibby, who's in NYU, takes a job working at a local video store, but her biggest concern is worrying that she might be pregnant after having sex with boyfriend Brian (LEONARDO NAM) for the first time.
Lena is enrolled at the Rhode Island School of Design, but still misses her former Greek boyfriend, Kostas (MICHAEL READY), years after they broke up. When she attends her grandfather's funeral, she's shocked to discover that Kostas is now married, apparently with a baby on the way. Her attention, however, is diverted -- and then some -- when she takes a figure drawing class and gets an eyeful of buff nude model, Leo (JESSE WILLIAMS).
At the same time, and feeling that she's growing apart from her pregnant mom (RACHEL TICOTIN), Yale student Carmen accepts the offer from school actress Julia (RACHEL NICHOLS) to work backstage at a Vermont production of "The Winter's Tale," directed by Bill (KYLE MacLACHLAN) and starring the charismatic lead actor, Ian (TOM WISDOM). Meanwhile, Bridget -- upset upon the discovery that her father (ERNIE LIVELY) hid letters to her from her maternal grandmother, Greta (BLYTHE DANNER) -- has traveled to Turkey to work on an archaeological site run by Professor Nasrin Mehani (SHOHREH AGHDASHLOO).
Despite resurrecting their former tradition of rotating those magic pants between them, the girls find themselves drifting apart, which isn't good considering that various developments in their lives mean they need each other's friendship more than ever.