Fran is the second daughter of Sylvia and Mortie Fine. She was raised in Flushing, Queens in New York City beside her older sister Nadine, who is very rarely seen. In her teens, Fran and her still best friend, Val Toriello, (As portrayed by actress Rachel Chagall) attended local Hillcrest High School alongside fellow students Ray Barone (a character from Everybody Loves Raymond, another CBS sitcom), Fran's arch rival Heather Biblow (played by Pamela Anderson), the late actress Morgan Faulkner (played by Jane Sibbett), and taxicab driver/wannabe playwright Jeffrey Needleman (played by actor Richard Kind).

After graduating high school, Fran attended Cosmetics or Beauty College (something which Fran Drescher actually did in real life) while working as a foot model. She worked in her then-fiance now ex-fiance's, Danny Imperioli's, bridal dress shop located in Flushing, until she was dumped by Danny Imperioli who immediately replaced her with Heather Biblow (at this point, the series started). Not only did Heather steal Fran's job, but she also married Danny. Fran resorted to selling "Shades of the Orient" cosmetics from door to door, where she becomes the nanny of the Sheffield family. Fran has a signature nasal-sounding voice, which has often made her the butt of jokes by people with whom she associates.

Throughout the entire series, Fran was shown as a bubbly, outgoing, and humorous character who appears to get into trouble often but usually ends up solving the problems herself in equally ridiculous ways. The show is loosely based on Francine Joy Drescher, who plays Francine Joy Fine. Her parents are really Sylvia and Morty Drescher, with a sister named Nadine. She actually lived in Flushing, and also went to Hillcrest High in Jamaica; Queens, although she was never a nanny.

In the show's pilot episode, Fran arrives at the home of Broadway producer Maxwell Sheffield (played by Charles Shaughnessy), who happens to be in desperate need of a nanny to take care of his three children: Margaret "Maggie" Sheffield, the oldest (played by Nicholle Tom), the youngest, Grace Sheffield (played by Madeline Zima), and the somewhat bratty middle brother, Brighton Sheffield (played by Benjamin Salisbury). Fran decides to show Mr. Sheffield her references, which are written in lipstick. Out of sheer desperation, Mr. Sheffield agrees to hire her. Fran, with her nontraditional nurturing style and no-nonsense honesty, soon becomes a favorite with the kids as well as Maxwell, as they come to respect her opinions and love her as a person.

Regretting her past break-up with her fiance Danny, Fran has often felt the need to date. At the turn of middle age, Fran is desperate to find a soul-mate. Fran is often attracted to Jewish men. This compelling desire of hers mainly comes from the obsessive, overbearing nature of her mother Sylvia, who often nags Fran about the subject of marriage.

The romantic tension between Maxwell and Fran lasts until the middle of the fifth season, when the couple are engaged; following several snafus, they are finally married in the season five finale. Until that point, they always address each other with proper employer-employee politeness, i.e. "Miss Fine" and "Mr. Sheffield".

Maxwell confesses to Miss Fine that he loves her when their plane to New York meets some turbulence, and he believes they may crash. Upon returning home, Maxwell immediately revokes the statement (this is later referred to as "The Thing" and is held over Mr. Sheffield's head with glee by Fran and Niles).

By the fifth season, Mr. Sheffield and Miss Fine begin a tentative romantic relationship, which consisted of a very large milestone: calling each other by their first names. Mr. Sheffield proposes marriage (a move that sends C.C. Babcock, who had an obsessive crush on Maxwell and jealous hatred of Fran, to an insane asylum), and they are married in the season 5 finale. Fran finally gives birth to fraternal twins, Jonah and Eve, in the series finale. Jonah, being named for Fran's side of the family, is more reserved like Maxwell. Eve, being named for Maxwell's side of the family, is more nasally and boisterous like Fran.

Despite the fact they stopped using each other's last names to address each other when they married, Fran and Max would still switch to their boss/employee roles out of habit. When Max is angry with her, he will instinctively shout "Miss Fine!", causing a worried Fran to reply, "Oh no, I'm Miss Fine again!". The same is true for Fran, who calls Maxwell "Mr. Sheffield" in bed. Before they got married, Fran had many fantasies of them kissing passionately. In one episode, a drunk Fran accidentally went to bed alongside a sleeping Max. Upon waking up to find where she was, she first said, "I'm havin' that dream again."