During her time at NYU, Heckerling was making mostly musicals. "I was the only one doing them and they were weird. It was the mid-70s and it was a bizarre combination of long hair with bell bottoms, the tail end of the hippie movement at its schlumpiest. With this, I sort of infused a 1930s idiotic grace that didn't go with the post-Watergate mentality that was prevalent at the time. They were weird films, but they got me into AFI."

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 has married twice, first to David Brandt in 1981. They were divorced in 1983. In 1984, Heckerling briefly married Director Neal Israel, though they divorced soon after. The couple had a daughter, Mollie Israel, in 1985. 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:

Heckerling's first feature was Fast Times at Ridgemont High (1982), based on the non-fiction account of a year-in-the-life of California high school students as observed by undercover Rolling Stone Journalist Cameron Crowe. When Heckerling first signed on to do a feature for Universal, she read a lot of scripts, but it was Crowe's script for Fast Times at Ridgemont High that really stuck out to her as a great script. She notes that the characters felt so real. Though she loved the script, she did feel that there was too much studio interference, so she read the novel, figured out which parts were strongest, and sat down with Crowe to rework the script. The film helped launch the careers of numerous stars including Phoebe Cates, Judge Reinhold, and Jennifer Jason Leigh. In addition, it marks early appearances by several actors who later became stars, including Nicolas Cage, then billing himself as Nicolas Coppola, Forest Whitaker, Eric Stoltz, and Anthony Edwards. Most notable, however, is the appearance of Sean Penn as Jeff Spicoli, who was launched into stardom with his iconic character. Heckerling describes casting Penn, whom she first met while he was sitting on the floor outside of the casting office, as a feeling of being overwhelmed by his intensity, even though all he had done was look up at her. She knew that this was her Spicoli, even though they had seen other people who had read better for the role. Penn had to do it. Ally Sheedy, whom Heckerling loved, read for the role of Leigh's character Stacy Hamilton, but Heckerling decided that she wanted someone that seemed younger and more fragile. Heckerling was very discriminating about the film's Soundtrack. Originally, the film was supposed to have music in it by bands like the Eagles.

After doing Fast Times at Ridgemont High, Heckerling was bombarded with similar but lesser scripts. It was hard for her to find anything that wasn't about high school, preppy kids, or story about a girl losing her virginity. Eventually she found her next film. Johnny Dangerously (1984), with Michael Keaton, Joe Piscopo, Danny DeVito, Dom DeLuise, and Peter Boyle, was an Airplane!-style spoof of gangster movies, but it failed to catch fire at the box office upon its initial release. Heckerling attributes the film's failure to the public's lack of familiarity with the gangster movies that the film was poking fun at. "It was pure satire of something nobody remembers. I think that was the main Problem, because all the actors and Writers did great jobs. But we were definitely satirizing something...I mean, unless you watch 1930s movies on TV at night, people don't remember. Somebody told me that during a screening they were sitting next to Brian De Palma, who had just done Scarface, and he was in hysterics. If you studied those movies, you know what we were doing." In subsequent years, however, it has garnered a substantial cult audience.

The following year, she directed National Lampoon's European Vacation (1985) with Chevy Chase and Beverly D'Angelo, a sequel to the popular National Lampoon's Vacation. With it, Heckerling scored her second solid hit, earning $74,964,621 at the box office. The film, like many of Heckerling's films, received poor reviews from critics but proved to be very popular with audiences who just wanted to watch a funny movie. Heckerling, despite being well educated and loving the work of such intellectual Writers at Franz Kafka admits that she loves "silly things", which has proven to make her commercially successful in the comedy genre.

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, 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.

Later in Heckerling's career, she decided that she just wanted to do what she loves. Heckerling directed and produced Loser (2000), a romantic college comedy with Jason Biggs and Mena Suvari. The film was not a critical or commercial success. After a break, Heckerling's romantic comedy I Could Never Be Your Woman (2007), starring Michelle Pfeiffer and Paul Rudd, never opened in theaters; rather, it received a direct-to-video release, despite fairly good notices. Production of the film was troubled by financial issues, including the rights to distribution being sold off without Heckerling's knowledge, making it difficult for her to sell the film to a studio. At the time, Heckerling was also taking care of both of her parents who were very ill (her father was in the hospital and her mother had cancer). Though Heckerling dislikes the baggage that the film carries and is upset about it not being released theatrically, she says that the experience was significant for her because she loved working with Rudd and Pfeiffer in England. Heckerling also directed an episode of the NBC version of The Office.

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.

Two Look Who's Talking sequels would follow—1990's Look Who's Talking Too—also directed by Heckerling and co-written with her then-husband Neal Israel. The film added another baby to storyline and was a moderate success. Heckerling then produced, but did not direct, the third and final sequel, Look Who's Talking Now—a flop. The films also spawned a brief television show called Baby Talk that was largely written by Heckerling.

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 will receive 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.

In an interview with Michael Singer, when asked about film's ability to grant a form of immortality, Heckerling describes the experience during the accident: "There was the whole thing-the yellow light and all that stuff-and what went through my mind right then was, ‘Well, at least I got the film to the lab.’ So it’s not going to save you from anything, obviously, but something about it pulls you forward." Eventually, she finished the film and held a screening that gained a very positive response, causing Heckering to call it one of the best days of her life. Her next step was to use the film to get a job. Tom Mount, President of Universal Pictures, showed a lot of interest in Heckerling but because she was not backed by an agent they could not hire her. After months of struggling to find an agent, Mount called Heckerling up on the phone and asked her to make a film.