Between 2000 and 2004, Pearce was the lead singer and guitarist in the London alt-country band Woodchuck.

In 2007, Pearce created the cult-hit series No Heroics, a sitcom about unsuccessful superheroes, following their R-rated off-duty exploits and their lives in hero-only pub The Fortress. The full series was shot in 2008, and released in October of that year. The show was ITV2’s first original sitcom. No Heroics was well reviewed by critics. The Times said of the show, “ITV2’s new comedy No Heroics is fast, funny and a little ingenious. Drew Pearce, the creator/writer, established an engaging collection of pretenders to the throne”. The show was nominated for Best New British TV Comedy of 2008 at the British Comedy Awards.

In 2009, ABC commissioned Pearce for an American adaptation pilot of No Heroics. Pearce was joined by Will & Grace writer Jeff Greenstein for the pilot.

In 2010, Marvel hired Pearce to write a feature adaptation of Runaways based on the comic book of the same name by Brian K. Vaughan and Adrian Alphona. Development on the film was put on hold the following October, and Pearce explained in September 2013 that the Runaways film had been shelved due to the success of The Avengers. Years later, Runaways would eventually be released as a web television series created for Hulu by Josh Schwartz and Stephanie Savage.

In March 2011, Marvel announced that Pearce would co-write Iron Man 3 with director Shane Black. Black described their take on the film as not being “two men in iron suits fighting each other,” and more like a “Tom Clancy thriller,” with Iron Man fighting real-world type villains. Pearce added that they would avert magic and space, with Iron Man 3 being “a techno-thriller set in a more real-world than even The Avengers.”

Pearce continued his work as a writer on a wide array of projects. Pearce also completed an uncredited rewrite on Guillermo del Toro’s sci-fi action thriller Pacific Rim. In October 2011, he was commissioned to write the script for a third film in the Sherlock Holmes film series starring Robert Downey Jr. The following year Pearce was tapped to polish the script for Legendary Pictures’ Godzilla reboot.

In March 2012, Pearce directed the music video for the song “Rearrange” by Miles Kane. By March 2018, it had received over 3.9 million YouTube views. Pearce went on to direct a video for the Father John Misty song “The Night Josh Tillman Came to Our Apartment”.

The film received positive reviews and was commercially successful, grossing over $1.2 billion worldwide, the second-highest-grossing film of 2013 overall, and the second-highest-grossing film at the domestic box office released in 2013.

In August 2013 Paramount Pictures announced the fifth Mission: Impossible film, from a script penned by Pearce. After developing the script with the director, Christopher McQuarrie, Pearce received a story by credit for Mission: Impossible – Rogue Nation. The film grossed $195 million in the U.S. and Canada, and $487.7 million in other countries, for a worldwide total of $682.7 million. It received critical acclaim, securing a Rotten Tomatoes score of 93% based on 291 reviews and an average rating of 7.5/10. The site’s critical consensus reads, “Mission: Impossible – Rogue Nation continues the franchise’s thrilling resurgence—and proves that Tom Cruise remains an action star without equal.”

All Hail the King was released on the digital download release of Thor: The Dark World on 4 February 2014, and on 25 February 2014 for the Blu-ray release. IGN’s Cliff Wheatley gave All Hail the King a 9.4 out of 10. He said that it is “a return to the loveable personality of the hapless Trevor and a step forward for the larger Marvel Cinematic Universe. It has its twists that should satisfy both lovers and haters of Trevor Slattery. But it’s the approach that Pearce takes with the material, from the kung-fu movie style credit sequences to the light-hearted tone that takes a sudden and jarring turn.”

Pearce then partnered with Jason Segel to create the concept for a third Lego Movie spin-off, titled The Billion Brick Race. In March 2015, Warner Bros. announced that the film was in development with its animation feature arm, Warner Animation Group. Pearce and Segel were initially signed on to co-direct and write the film, however, both subsequently stepped away from those roles. On February 8, 2018, they returned to the project when it was revealed that the initial director, Jorge R. Gutierrez, left it.

Two-time Academy Award winner Jodie Foster starred in the film, alongside an ensemble cast, including Sterling K. Brown, Dave Bautista, Sofia Boutella, Jeff Goldblum, Jenny Slate, Charlie Day, Zachary Quinto, Brian Tyree Henry and Kenneth Choi. Filming began in Los Angeles in May 2017, and Hotel Artemis was released on 8 June 2018 in North America, by Global Road Entertainment.

In 2018 Pearce established production company Point of No Return Films in Los Angeles, California. The company focuses on developing and producing film and television projects aimed at reinventing genre. Its first production was Pearce’s directorial debut, Hotel Artemis. On June 26, 2019, Variety (magazine) announced that Netflix acquired Pearce’s next film, Quartermaster, which Point of No Return will produce alongside Adam Siegel of Marc Platt Productions. It will be a “high-concept thriller” that Pearce is slated to write and direct.