In 1996, Garland's first novel, The Beach was published. The Beach is based upon Garland’s own travels across Europe and the Philippines, it tells the story of a young English backpacker who discovers an unspoiled sea shore occupied by a community of like-minded backpackers. The novel is noted for its references to drug culture, sequences of hallucinations and unique depictions of excess and utopia, which have been commended by critics. The Beach was initially met with positive reviews, and with a spreading word of mouth response the novel grew into a cult classic. Garland would later speak of the overwhelming discomfort with the fame The Beach had allowed him to achieve, “I never felt comfortable with it (the novel).” The Beach has been translated into 25 different languages and sold close to 700,000 copies by the start of 1999. It would later be developed into a film starring Leonardo DiCaprio.

In 1998, Garland followed up The Beach with The Tesseract, a non-linear narrative with several interwoven characters set in Manila, Philippines. The novel is characterized by a post-modernist narrative style and structure. It explores several themes such as love and violence through each character’s circumstance and context of surroundings as well as seemingly inconsequential actions and the repercussions of those actions on other characters. The Tesseract did not enjoy the critical or commercial success of The Beach, but it too was the subject of a film adaptation.

In 2002, he wrote the screenplay for Danny Boyle's 28 Days Later, starring Cillian Murphy. He won a Best Screenplay honor at the 2004 Fangoria Chainsaw Awards for his script of the film. In 2005, Garland wrote a script for a film adaptation of Halo; he was paid $1 million. D. B. Weiss and Josh Olson rewrote this during 2006 for a 2008 release, though the film was later cancelled. In 2007, he wrote the screenplay for the film Sunshine – his second screenplay to be directed by Danny Boyle and to star Cillian Murphy. Garland served as an executive Producer on 28 Weeks Later, the sequel to 28 Days Later. He wrote the screenplay for the 2010 film Never Let Me Go, based on the novel by Kazuo Ishiguro. He also wrote the script for Dredd, an adaptation of the Judge Dredd comic book series from 2000 AD. In 2018, Karl Urban, who played the eponymous role in the film, stated that it was Garland who deserved credit for also directing Dredd.

Garland is the co-writer on the video game Enslaved: Odyssey to the West for the PlayStation 3 and Xbox 360. For his writing work on the game, he won a 2011 award from the Writer's Guild of Great Britain (along with co-writer Tameem Antoniades). Garland also served as a Story Supervisor on the game DmC: Devil May Cry in 2013.

Garland made his credited directorial debut with Ex Machina, a 2015 feature film based on his own story and screenplay. The film stars Domhnall Gleeson, Alicia Vikander and Oscar Isaac. The film won a Jury Prize at the 2015 Gerardmer Film Festival and earned Garland a nomination for an Academy award for best original screenplay. The film's lead Actress, Alicia Vikander, was nominated for a Best Actress award at the Empire Awards.

Garland's second film, Annihilation (2018), was based on Jeff VanderMeer's 2014 science fiction novel of the same name. Garland has described it as "an adaptation which was a memory of the book," rather than book-referenced screenwriting, to capture the "dream like nature" and tone of his reading experience. Production began in 2016, and the film was released in February 2018.