Originally set in an apartment building in New York City, I Love Lucy centers on Lucy Ricardo (Lucille Ball) and her singer/bandleader husband, Ricky Ricardo (Desi Arnaz), along with their best friends and landlords, Fred Mertz (William Frawley) and Ethel Mertz (Vivian Vance). During the second season, Lucy and Ricky have a son named Ricky Ricardo Jr. ("Little Ricky"), whose birth was timed to coincide with Ball's real-life birth of her son, Desi Arnaz Jr.

Lucy is naïve and ambitious, with a zeal for stardom and a knack for getting both herself and her husband into trouble whenever she yearns to make it in show business. The Ricardos' best friends, Fred and Ethel, are former vaudevillians. The Mertz's history in entertainment only strengthens Lucy's resolve to prove herself as a performer, though she often feels excluded, as her industry involvement is limited, relative to that of Ricky, Fred, and Ethel. Though charismatic, throughout the series, she is depicted as having few marketable performance skills, and she is often portrayed as being tone deaf, struggling to sing anything other than off-key renditions of songs such as "Glow Worm" on the saxophone, and many of her performances end in disaster. However, to say she is completely without talent would be untrue, as on occasion, she is shown to be a good dancer and a competent singer. She is also at least twice offered contracts by television or film companies—first in "The Audition", when she replaces an injured clown in Ricky's act at the Tropicana nightclub, and later in "Lucy and the Dummy", when she dances in Hollywood for a studio party using a rubber Ricky dummy as her dancing partner.

The show provided Ball ample opportunity to display her considerable skill at clowning and physical comedy. Character development was not a major focus of early sitcoms, however, so little information was offered about her life before the show. A few episodes mentioned that she was born in Jamestown, New York (Lucille Ball's real-life home town), later changed to West Jamestown, that she graduated from Jamestown High School, that her maiden name was "McGillicuddy" (indicating a Scottish or Irish ethnicity, at least on her father's side, though she once mentioned her grandmother was Swedish), and that she met Ricky on a boat cruise with her friend from an agency she once worked for. Her family was absent, other than occasional appearances by her scatter-brained mother (Kathryn Card), who could never get Ricky's name right. Lucy also exhibited many traits that were standard for female comedians at the time, including being secretive about her age and true hair color, and being careless with money, along with being somewhat materialistic, insisting on buying new dresses and hats for every occasion and telling old friends that she and Ricky were wealthy. She was also depicted as a devoted housewife, adept cook, and attentive mother. As part of Lucy's role was to care for her husband, she stayed at home and took care of the household chores, while her husband Ricky went to work. During the post war era, Lucy took jobs outside of the home, but in these jobs, the show portrayed her as being inept outside of her usual domestic duties.