Mary Richards (Moore) is a single woman who, at age 30, moves to Minneapolis on the heels of a broken engagement. She applies for a secretarial job at fictional television station WJM, but the position is already taken. She is instead offered the post of associate producer of the station's six o'clock news. She befriends tough but lovable boss Lou Grant (Ed Asner), newswriter Murray Slaughter (Gavin MacLeod), and buffoonish anchorman Ted Baxter (Ted Knight). Mary is later promoted to producer of the show, though her duties remain the same.

Mary rents a third-floor studio apartment in a 19th-century house from acquaintance Phyllis Lindstrom (Cloris Leachman); Mary and upstairs neighbor Rhoda Morgenstern (Valerie Harper) become best friends. Characters introduced later in the series include the acerbic, man-hungry hostess of WJM's Happy Homemaker show, Sue Ann Nivens (Betty White), and soft-voiced, sweet-natured Georgette Franklin (Georgia Engel), as Ted Baxter's girlfriend (and eventual wife). At the beginning of season 6, after both Rhoda and Phyllis have moved away (providing a premise for two spinoffs), Mary relocates to a one-bedroom apartment in a high-rise building; Minneapolis's Riverside Plaza was used for establishing shots.

From the beginning, issues such as workplace discrimination against women figured into episode stories. In the third season, issues such as equal pay for women, pre-marital sex, and homosexuality are woven into the show's comedic plots. In season four, marital infidelity and divorce are explored with Phyllis and Lou, respectively. In the fifth season, Mary refuses to reveal a news source and is jailed for contempt of court. While in jail, she befriends a prostitute (Barbara Colby) who seeks Mary's help in a subsequent episode. In the highly rated sixth-season episode "The Seminar", Betty Ford makes history by becoming the first First Lady to appear on a television sitcom in a cameo role. The show's final seasons explore death in "Chuckles Bites the Dust" and juvenile offenders in "Mary's Delinquent"; Ted suffers a heart attack; Ted and Georgette contend with intimate marital problems, deal with infertility, and adopt a child; and Mary overcomes an addiction to sleeping pills. Mary dates many men on and off over the years but remains single throughout the series.

One of the show's running gags is Mary's inability to throw a successful, problem-free party. Various disasters throughout the seasons include the break-up of two of Mary's closest friends; an insufficient amount of food due to unexpected guests; a power failure while attendees await the arrival of a high-profile guest of honor (Johnny Carson); and the birth of Ted and Georgette's baby.[