When Zoe is alerted by the Health Department about a flu epidemic heading towards BlueBell, she is forced to put the town on lock down. Because of the quarantine, Wade is forced to stay at his ex-girlfriends house causing Zoe to become jealous. Lemon's plan for the perfect night with Walt goes awry when she begins to feel under the weather. Meanwhile, George finds himself roped into directing Lavon's tourism commercial about BlueBell's small-town charm, but it seems Lavon, is more preoccupied with his co-star than his commercial.
Fast-talking New Yorker and brand new doctor Zoe Hart has it all figured out - after graduating top of her class from medical school, she'll follow in her father's footsteps and become a cardio-thoracic surgeon. But when her dreams fall apart, Zoe decides to accept an offer from a stranger, Dr. Harley Wilkes, to work with him at his small practice in Bluebell, Alabama. Zoe arrives in this small Gulf Coast town only to find that Harley has passed away and left his half of the medical practice to her in his will.
She quickly finds that Southern hospitality isn't always so hospitable - the other doctor in town, Brick Breeland, is less than pleased to be sharing the practice with this young outsider, and his daughter, Lemon, is a Southern belle whose sweet disposition turns sour when she meets Zoe. Zoe's only allies are the mayor, former football star Lavon Hayes, her bad-boy neighbor Wade Kinsella, and handsome lawyer George Tucker - who just happens to be Lemon's fiance. Zoe is out of her element and ready to pack her bags, but a surprise visit by her snobby New York mother leads to Zoe's decision to stay in Bluebell for a while, discovering small-town life and a side of herself she hadn't known was there.