She graduated from high school in 1970, focused on directing and studying film at New York University’s Tisch School of the Arts. Her father made just slightly over the cut-off for financial aid for the school, so Heckerling had to take out a large loan to cover her expenses. She claims this caused considerable stress in her life, and she was unable to pay them off until the end of her twenties. When Heckerling was in high school and focused on directing, her father was opposed to the idea, wishing that she had chosen a more practical aspiration. Despite this, he gave her Parker Tyler’s book Classics of the Foreign Film: A Pictoral Legacy. Heckerling pored over the book, marking off films that she had seen until she had eventually watched most of them. She claims that by the time she got to NYU, because of this book, she had seen almost all of the films that they had to watch in her classes. Though Heckerling considered her time at NYU to be a great time where she learned a lot and made great connections, such as Martin Brest and noted screenwriter and satirist Terry Southern who was one of her professors, she later reflects on her time at the school as sloppy and unprofessional, claiming that she used very low-quality equipment and had a lot of technical problems.

Heckerling dated friend and fellow film director Martin Brest briefly when she first moved to Los Angeles. Though they later broke up, they remained good friends. Heckerling’s first marriage was to David Brandt, from 1981 to 1983. In 1984, Heckerling married director Neal Israel, but divorced in 1990. The couple’s daughter, Mollie Israel, was born in 1985. Mollie was led to believe Israel was her biological father until 2004, when it was revealed to her that in fact Harold Ramis was her biological father. Heckerling has included Mollie in some of her films in bit parts, including Look Who’s Talking and Loser, though Heckerling claims that her daughter never wanted to be a “girly girl” and distanced herself from much of her work, never adding any input to the lives of characters such as those in Clueless. Despite this, the two get along very well and Mollie frequently introduces her mother to new music, such as OK Go and films. Today Mollie sings in the band The Lost Patrol. Heckerling lives in both Los Angeles and New York and continues to make films and do what she loves. Heckerling is one of the few women to have directed multiple box-office hits. When asked about the fact that only 5% of movies are directed by women, Heckerling states:

In 1989, Heckerling had her biggest success with Look Who’s Talking, starring John Travolta, Kirstie Alley and a baby voiced by Bruce Willis. Heckerling got the idea for the film while she was pregnant with her daughter and further developed it into a feature. Heckerling says that she loves to write comedies, such as Look Who’s Talking, because she notes that when a film is made, everyone working on it puts more than a year of their lives into making it, so she wants that year to be happy and fun. Heckerling, who loves Travolta, was ecstatic to work with him, though many people consider the film’s release to be during the end of a low point in Travolta’s career. The film has been Heckerling’s highest-grossing film to date, earning $296,999,813. After the film’s release, Heckerling was able to cross one of her two goals that she set for herself in college off of her list, the first being to make a studio feature, which she did with Fast Times at Ridgemont High and the second being: “I wanted to have hits the way boys had hits, not like a ‘girl hit’ that made 50 million, but a boy hit that made 100s of million.”

In 1995, she wrote and directed Clueless, reworking and updating Jane Austen’s Emma as a 1990s teen comedy about wealthy teenagers living in Beverly Hills. Heckerling originally thought of Clueless as a television show because she loved to write the character of Cher who she described as a “happy, optimistic, California girl”, and wanted to explore all of her adventures, but after she pitched it to her agent she was told that it would make a great feature. To research for the script, Heckerling sat in on classes at Beverly Hills High School where she observed how teenagers acted, though she admits that most of it was made up. She notes that teenagers at the high school did not dress in high fashion every day as the characters do in the film and that in reality the students there dressed just as frumpily as everyone else. She did, however draw on many of her observations, especially the tendency of teenage girls to groom themselves constantly. “You would think that within, you know, the few minutes that they’ve been in class, that their makeup wouldn’t be needing so much repair and yet they’re constantly painting and sculpting and … doing to themselves.” As with Fast Times at Ridgemont High, it quickly caught on with teenagers and went on to become a significant pop culture reference point. The film went on to gross $56,631,572 and helped launch the careers of most of the cast, including Alicia Silverstone, Brittany Murphy, Paul Rudd, Donald Faison, Breckin Meyer, and Stacey Dash. It was spun off into a moderately successful TV series, with Heckerling penning the pilot, as well as directing several episodes from the first season. Heckerling describes the show as basically the same as the film, only cleaner, and says that she still loves the characters.

In 1995, Heckerling won the National Society of Film Critics Best Screenplay award and was nominated for the Writers Guild of America award for Best Screenplay Written Directly for the Screen for her screenplay, Clueless. In 1998, she received the Franklin J. Schaffner Medal from the American Film Institute. In 1999, she received the Women in Film Crystal Award for outstanding women who, through endurance and excellence, have helped to expand the role of women within the entertainment industry.

In 2011, Heckerling directed the horror-comedy film Vamps with Sigourney Weaver, Alicia Silverstone and Krysten Ritter, about two vampires living in New York City as best friends and roommates. The film was released to theatres on November 2, 2012, followed by a DVD release on November 13.

On July 4, 2016, Gilbert Gottfried posted an in-depth 81-minute interview with Heckerling on his podcast.

In July 2017, a musical version of Clueless helmed by Tony nominee Kristin Hanggi received a developmental lab in New York City. A previous workshop starring Taylor Louderman (Kinky Boots) and Dave Thomas Brown (Heathers) took place in 2016. Heckerling wrote the libretto for the musical. The musical opened Off-Broadway on November 20, 2018.

Actor and comedian Chris Kattan claimed in his 2019 memoir Baby, Don’t Hurt Me: Stories and Scars from Saturday Night Live that he was pressured by Lorne Michaels to have sex with Heckerling so she would direct the 1998 film A Night at the Roxbury (although she ultimately only produced, rather than directed it). Heckerling’s daughter Mollie disputes his claims saying that, although Heckerling and Kattan had an affair, it was when the film was already shooting.