Garfield began taking acting classes in Guildford, Surrey, when he was 9, and appeared in a youth theatre production of Bugsy Malone. He also joined a small youth theatre workshop group in Epsom and took Theatre Studies at A-level before studying for a further 3 years at a UK conservatoire, the Central School of Speech and Drama. Upon graduating in 2004 he began working primarily in stage acting. In 2004 he won a Manchester Evening News Theatre Award for Best Newcomer for his performance in Kes at Manchester’s Royal Exchange Theatre (where he also played Romeo the year after), and won the Outstanding Newcomer Award at the 2006 Evening Standard Theatre Awards. Garfield made his British television debut in 2005 appearing in the Channel 4 teen drama Sugar Rush. In 2007 he garnered public attention when he appeared in the series 3 of the BBC’s Doctor Who, in the episodes “Daleks in Manhattan” and “Evolution of the Daleks”. Garfield commented that it was “an honour” to be a part of Doctor Who. In October 2007, he was named one of Variety’s “10 Actors to Watch”. He made his American film debut in November 2007, playing an American university student in the ensemble drama Lions for Lambs, with co-stars Tom Cruise, Meryl Streep and Robert Redford. “I’m just lucky to be there working on the same project as them, although I don’t really expect to be recognized later by audiences,” Garfield told Variety in 2007. In his review for The Boston Globe, Wesley Morris considered Garfield’s work “a willing punching bag for the movie’s jabs and low blows”.

In the Channel 4 drama Boy A, released in November 2007, he portrayed a notorious killer trying to find new life after prison. The role garnered him the 2008 British Academy Television Award for Best Actor. Amy Biancolli of the Houston Chronicle wrote that “there is no doubt about the intelligence and sensitivity” of Garfield’s portrayal. Minneapolis Star Tribune’s Christy DeSmith echoed Biancolli’s sentiment, citing his “detailed expressions” as an example. Writing in The Seattle Times, John Hartl noted that Garfield demonstrated range in the role, and concluded: “Garfield always manages to capture his passion”. Joe Morgenstern, the critic for The Wall Street Journal, dubbed Garfield’s performance “phenomenal”, assessing that he “makes room for the many and various pieces of Jack’s personality”. In 2008, he had a minor role in the film The Other Boleyn Girl, and was named one of the Shooting Stars at the Berlin International Film Festival. In 2009, Garfield held supporting roles in the Terry Gilliam film The Imaginarium of Doctor Parnassus and the Red Riding television trilogy. Kenneth Turan of the Los Angeles Times thought that Garfield gave a stand out performance in the latter.

Garfield has dual citizenship in the United States and the United Kingdom. In 2009, he told the Sunday Herald that he “feels equally at home” in both the United States and the United Kingdom and “enjoys having a varied cultural existence”. Garfield customarily gives interviews about his work, but does not publicly discuss details of his private life.

In 2010, Garfield co-starred opposite Carey Mulligan and Keira Knightley in Mark Romanek’s dystopian science fiction drama Never Let Me Go, an adaptation of Kazuo Ishiguro’s 2005 novel of the same name. He said of his character, Tommy D., “There’s a sense of anxiety that runs through these kids, especially Tommy, because he’s so sensory and feeling and animalistic, that’s my perspective of him.” Garfield was attracted to the film based on the existential questions the story expresses. He said the experience of being a part of Never Let Me Go was “just a dream to come true”. He further remarked that the scenes in which his character—unable to contain his frustration—erupts with a wail, were “intense” for him. “I think those screams are inside all of us, I just got a chance to let mine out”. For his portrayal of a well-meaning, but dim young man caught in a love triangle, he won the 2010 Saturn Award for Best Supporting Actor. Writing for Entertainment Weekly, Owen Gleiberman praised the performances of the lead cast, reflecting that “these three all act with a spooky, haunted innocence that gets under your skin.” In comparison to Mulligan and Knightley, Scott Bowles, writing for USA Today, deemed Garfield “the real find” of Never Let Me Go.

In 2011, Garfield began dating his The Amazing Spider-Man co-star Emma Stone sometime during production of the film. In 2015, they were rumoured to have broken up although no formal statement was released. When asked about his sexuality, Garfield identified himself as heterosexual but has said that he has “an openness to any impulses that may arise within me at any time”.

In 2011, Garfield became the Ambassador of Sport for the Worldwide Orphans Foundation (WWO).

In March 2012, Garfield made his Broadway theatre debut as Biff Loman in the revival of Death of a Salesman. According to The New York Times’s David Rooney, Garfield had successfully “exposed the raw ache of Biff’s solitude”. Garfield was nominated for a Tony Award for Best Featured Actor in a Play for his performance. Two years later, Garfield hosted an episode of Saturday Night Live and appeared in a music video for the song “We Exist” by Arcade Fire, playing a trans woman. Also in 2014, he co-produced and starred in the 2014 independent drama 99 Homes and reprised the titular role in The Amazing Spider-Man 2. Following a deal between Sony and Marvel Studios to integrate the Spider-Man character into the Marvel Cinematic Universe, sequels to the latter film were scrapped, and the role was later taken on by Tom Holland in a reboot. Arachnologists Yuri M. Marusik and Alireza Zamani honored Garfield’s portrayal of the role by naming a new species of crevice weaver spider, Pritha garfieldi, after him.

Garfield played the role of Prior Walter in Tony Kushner’s two-part play Angels in America at the National Theatre, London in the Lyttelton Theatre from April to August 2017, and the performance was broadcast live to cinemas around the world in summer 2017 through the National Theatre Live series. It was directed by Marianne Elliott and co-starred Nathan Lane, James McArdle, Russell Tovey and Denise Gough. Paul T Davis of The British Theatre Guide wrote that Garfield was “transformative and unrecognisable in places, completely inhabiting camp, laconic, frightened and totally loveable Prior Walter”. He was nominated for an Olivier Award for Best Actor.

Garfield’s sole film release of 2017 was the biopic Breathe, in which he portrayed Robin Cavendish, a young man paralysed by polio. In preparation, he interacted with victims of the disease and collaborated closely with Cavendish’s wife and son. Stephen Dalton of The Hollywood Reporter wrote that despite an exceptional story, the film had glossed over the complexities in Cavendish’s life, and thought that Garfield was “hampered by a role that restricts him to little more than nodding and grinning”. In March 2018, Garfield reprised the role of Prior when the Angels in America production transferred to Broadway for an 18-week limited engagement at the Neil Simon Theatre, alongside a majority of the London cast. Reviewing the production for The Washington Post, Peter Marks commented that “nothing [Garfield’s] done prepares you for the star-powered dexterity of his Prior” and considered his performance to be the “persuasive moral core of the piece”. He won the Tony Award for Best Actor in a Play for his performance.

The 2018 Cannes Film Festival marked the premiere of Garfield’s next film, the David Robert Mitchell-directed neo-noir Under the Silver Lake. In it, he played Sam, an unemployed and wayward young man who sets out on a journey to find his neighbour who has mysteriously disappeared. Writing for Vanity Fair, Richard Lawson found Garfield to be “great in the role, doing nimble, subtle bits of physical comedy and teasing out the creepy, menacing side of Sam”.