Kelley was born in Waterville, Maine, raised in Belmont, Massachusetts, and attended the Belmont Hill School. He is the son of Boston University Terriers and New England Whalers hockey coach Jack Kelley, and played the game himself. Kelley was a stick boy for the Whalers during his father's time as coach, and the captain of the hockey team at Princeton University, from which he graduated in 1979 with a bachelor's degree in political science.

In 1983, while considering it only a hobby, Kelley began writing a screenplay, a legal thriller, which was optioned in 1986 and later became the Judd Nelson feature film From the Hip in 1987.

In 1986, Steven Bochco was searching for Writers with a law background for his new NBC legal series, L.A. Law. His agent sent him Kelley's movie script for From the Hip. Enthusiastic, Bochco made him a Writer and story Editor for the show. During this first year, Kelley kept his law office in Boston as a hedge. However, his involvement in the show only expanded. In the second year, he became executive story Editor and co-producer. Finally, in 1989, Bochco stepped away from the series making Kelley the executive Producer. While executive Producer, Kelley received two Emmys for Outstanding Writing in a Dramatic Series and the show received the award for Outstanding Drama Series for both years. For the first five seasons that he was involved with the show, he wrote or co-wrote two out of three episodes. Kelley left after the fifth season in 1991 and ratings began to fall. As Newsday's TV critic wrote, "The difference between good and bad L.A. Law ... was David Kelley." Midway through the sixth season, both Bochco and Kelley were brought in as creative consultants after the show received bad press about its decline in quality.

Kelley has incorporated religious subject matter from the beginning, including issues involving Protestantism, Judaism, Scientology and Catholicism among others. With the widespread media coverage of child sexual abuse cases in the Roman Catholic Church during the mid-to-late 1990s, Kelley began to introduce this controversy into his scripts. For instance, the character Bobby Donnell on The Practice, a Catholic, became personally estranged from the Church over the issue of sexually abusive Priests. While the conservative Catholic League did not object to this episode, they frequently complained of anti-Catholic bias in Kelley's shows because of his references to this subject.

In 1992, after co-creating Doogie Howser, M.D. with his mentor Steven Bochco, Kelley formed his own production company, David E Kelley Productions, making a three-series deal with CBS. Its first creation, Picket Fences, airing in 1992 and influenced by Twin Peaks and Northern Exposure, focused on the police department in the fictional quirky town of Rome, Wisconsin. Kelley wrote most of the episodes for the first three years. The show was critically acclaimed but never found a sizable audience. Picket Fences went on for four years, receiving a total of 14 Emmy awards including consecutive Emmys for Outstanding Drama Series for its first and second seasons.

Michelle Pfeiffer had entered into private adoption proceedings before she met Kelley. In March 1993, she adopted a newborn daughter Claudia Rose. They married on November 13, 1993, and christened Claudia the same day. In August 1994, Pfeiffer gave birth to a son, John Henry.

Under pressure from CBS to develop a second series even though he didn't feel ready to produce two shows simultaneously, Kelley launched the medical drama Chicago Hope, starring Mandy Patinkin and Adam Arkin, which premiered in 1994. Airing at the same time as the season's other new medical drama, NBC's ER, the ultimate ratings leader, Chicago Hope plotted "upscale Medicine in a high-tech world run by high-priced doctors". During its six-year run, it won seven Emmys and generally high critical praise, but only middling ratings.

In 1995, Kelley entered into a five-year deal with 20th Century Fox Television to produce shows for both the ABC and FOX television networks, each agreeing to take two series. If one network passed on a project, the other got first refusal. Kelley retained full creative control. Ally McBeal on FOX and The Practice on ABC were the first two projects to come from this deal.

Besides his first film, From the Hip, which received poor reviews, Kelley wrote and produced three other films. 1996's To Gillian on Her 37th Birthday, a romance, co-starring his wife, Michelle Pfeiffer, received tepid critical and box office reception. In 1999, came two films: Lake Placid, a combination of suspense, horror and comedy, and Mystery, Alaska, about a fictional small-town ice hockey team that plays a game against the New York Rangers of the National Hockey League. Neither movie did well with either the critics or the audience.

When Ally McBeal premiered in 1997 on FOX, Kelley was also shepherding his other two shows, Chicago Hope and The Practice, although he was not actively participating in Chicago Hope at the time. The title character Ally is a young, attractive, impulsive, Harvard-educated Lawyer described by a New York Times Journalist as "stylish, sexy, smart, opinionated, and an emotional wreck." In contrast to The Practice and its idealistic lawyers, the law firm in Ally McBeal was founded only to make money.

Premiering on FOX in 2000, Boston Public, which follows the lives of teachers and administrators at a Boston high school, joined The Practice and Ally McBeal for the season, meaning Kelley was responsible for writing or overseeing 67 episodes.

In addition to Snoops, Kelley continued to have a string of unsuccessful series: girls club in 2002, The Brotherhood of Poland, New Hampshire in 2003 and the reality show The Law Firm in 2005. All the while, he continued overseeing Boston Public and The Practice.

In 2003, due to sagging ratings, ABC cut Kelley's budget in half for the eighth and final season. He responded by firing most of the cast and hiring James Spader for the role of Alan Shore, whom The New York Times described as "a lecherous, twisted antitrust Lawyer with a breezy disregard for ethics." The final episodes of The Practice were focused on introducing the new characters from his next show, Boston Legal.

Boston Legal on ABC, premiering in 2004, gave continuity and success to the Kelley franchise. It was a spin-off of his long-running legal drama The Practice, and followed attorney Alan Shore (a character who became the star of The Practice in its final season, played by James Spader) to his new law firm, Crane, Poole & Schmidt. It also starred veteran television actors Candice Bergen and william Shatner. Critically popular with less than spectacular ratings (ranked 27th for the first season, 46th for the second), the show was an "Emmy darling" during its run, winning seven times and being nominated over 25 times. The show won the Peabody Award in 2005 for its signature political commentaries.

The Wedding Bells premiered in fall 2007 and was canceled after seven episodes. Additionally, Kelley worked on an Americanized version of the BBC show Life on Mars for the 2007–2008 season on ABC and also worked on an adaptation of Joseph Wambaugh's Hollywood Station. He later handed off production to another creative crew.

The fifth and final season began in 2008 with Kelley writing most of the episodes. The season only aired thirteen episodes, making a series run of 101 episodes. The 2-hour series finale drew 11 million viewers. Still, the show drew over 15 million viewers much of its first season—and Kelley felt ABC's treatment of the show over the years ultimately killed it, saying to TV Guide that ABC always treated the show like its "bastard child." Boston Legal aired on four different nights (Sunday, Tuesday, Wednesday and Monday) in its five-season run, with the ratings slipping after each move. In the second-to-last episode of the series, Kelley blatantly wrote a show questioning the legitimacy of the Nielsen ratings and the network's treatment of the show by including a plot about a lawsuit against an unnamed television network.

Demonstrating early on a creative and quirky bent, in his junior year at Princeton, Kelley submitted a paper for a political science class about John F. Kennedy's plot to kill Fidel Castro, written as a poem. For his senior thesis, he turned the Bill of Rights into a play. "I made each amendment into a character", he said. "The First Amendment is a loudmouth guy who won't shut up. The Second Amendment guy, all he wanted to talk about was his gun collection. Then the 10th Amendment, the one where they say leave the rest for the states to decide, he was a guy with no self-esteem." Also while at Princeton, he was a member of the Princeton Triangle Club.

In 2011, Kelley wrote a script for the pilot episode of a new Wonder Woman TV series for Warner Bros. Television, but the pilot was rejected by NBC for its fall 2011 lineup.

A new comedy series created by Kelley, The Crazy Ones, starring Robin Williams and Sarah Michelle Gellar, premiered on CBS on September 26, 2013. The show was cancelled after a season due to lukewarm reception.

In 2014, David E. Kelley was inducted into the Television Hall of Fame.

In 2015, Kelley created the Amazon Studios series Goliath.

In 2017, Kelley spearheaded a new HBO series, Big Little Lies. He is also a showrunner on the TV adaptation of the Stephen King novel, Mr. Mercedes.