Rachel Green flees her wedding day and seeks out childhood friend Monica Geller, a New York City chef. They become roommates, and Rachel joins Monica's social circle of single people in their mid-20s: struggling actor Joey Tribbiani, business professional Chandler Bing, masseuse and musician Phoebe Buffay, and newly divorced paleontologist Ross Geller, Monica's older brother. To support herself, Rachel becomes a waitress at Central Perk, a Manhattan coffeehouse where the group often hangs out; when not there, the six are usually at Monica and Rachel's nearby West Village apartment, or Joey and Chandler's across the hall.

Episodes typically depict the friends' comedic and romantic adventures and career issues, such as Joey auditioning for roles or Rachel seeking jobs in the fashion industry. The six characters each have many dates and serious relationships, such as Monica with Richard Burke and Ross with Emily Waltham. Ross and Rachel's intermittent relationship is the most often-recurring storyline; during the ten seasons of the show they repeatedly date and break up, even while Ross briefly marries Emily, he and Rachel have a child, Chandler and Monica date and marry each other, and Phoebe marries Mike Hannigan. Other frequently recurring characters include Ross and Monica's parents in Long Island, Ross's ex-wife and their son, Central Perk barista Gunther, Chandler's ex-girlfriend Janice, and Phoebe's twin sister Ursula.