Wood achieved international fame in the early 2000s for playing the hobbit Frodo Baggins in Peter Jackson's The Lord of the Rings film trilogy (2001–2003), based on the classic fantasy novel of the same name by English author J. R. R. Tolkien.

As an adult, Wood appeared in a wide range of films, including Eternal Sunshine of the Spotless Mind (2004), Paris, je t'aime (2006), and I Don't Feel at Home in This World Anymore (2017).

Wood's parents sold their delicatessen in 1989 and the family, without his father, moved to Los Angeles to allow him to pursue an acting career; they divorced when he was 15.

"[12] Playing Aidan Quinn's son in Avalon garnered professional attention for Wood; the film received widespread critical acclaim and was nominated for four Academy Awards.

[13] A small part in Richard Gere's Internal Affairs was followed by the role of a boy who brings estranged couple Melanie Griffith and Don Johnson back together in Paradise (1991).

In 1992, Wood co-starred with Mel Gibson and Jamie Lee Curtis in Forever Young,[14] and with Joseph Mazzello in Radio Flyer.

[15] In 1993, Wood played the title character in Disney's adaptation of Mark Twain's novel, The Adventures of Huck Finn, and co-starred with Macaulay Culkin in the psychological thriller The Good Son.

"[18] Wood's title role—opposite Bruce Willis—in the Robert Reiner film North (1994) was followed by a Super Bowl commercial for Lay's "Wavy" potato chips (with Dan Quayle).

[19] In 1995, Wood appeared in the music video for The Cranberries' "Ridiculous Thoughts",[20] played the lead role in Flipper, and co-starred in Ang Lee's critically acclaimed The Ice Storm.

In 1997, Wood played Jack "The Artful Dodger" Dawkins in a made-for-TV adaptation of Oliver Twist, alongside Richard Dreyfuss.

[33] Wood's first role following his Lord of the Rings success was in Eternal Sunshine of the Spotless Mind (2004), in which he played Patrick, an unscrupulous lab technician who pursues Kate Winslet.

He next played the silent serial killer Kevin in Robert Rodriguez's adaptation of Frank Miller's comic book series, Sin City (2005).

[35] In Everything Is Illuminated (2005), Wood starred as a young Jewish-American man on a quest to find the woman who saved his grandfather during World War II.

[38] In George Miller's animated musical Happy Feet (2006), Wood provided the voice of Mumble, a penguin who can tap dance, but not sing.

Wood, along with his co-stars, received a nomination for the Screen Actors Guild Award for Outstanding Performance by a Cast in a Motion Picture.

[42] Later that year, Wood hosted the television special Saving a Species: The Great Penguin Rescue for Discovery Kids;[43] he received a nomination for the Daytime Emmy Award for Outstanding Performer in Children's Programming.

"[59] In 2012, Wood had a supporting role in the romantic comedy Celeste and Jesse Forever, and starred in the horror film Maniac, for which he received the Fangoria Chainsaw Award for Best Actor.

[66] From 2016 to 2017, Wood co-starred with Samuel Barnett as Todd Brotzman in the BBC America series Dirk Gently's Holistic Detective Agency.

[70] In 2023, Wood played the starring role of Fritz Garbinger in Macon Blair's superhero comedy horror movie The Toxic Avenger, one of a series.

On April 25, 2009, he was honored with the Midnight Award by the San Francisco International Film Festival as an American actor who "has made outstanding contributions to independent and Hollywood cinema, and who brings striking intelligence, exemplary talent and extraordinary depth of character to his roles.

[76] Wood signed up to co-produce and star in the film Black Wings Has My Angel, based on the noir novel of the same name, with Anthony Moody and Rob Malkani of Indalo Productions.

[77] Wood together with Sean Astin, Sean Bean, Orlando Bloom, Billy Boyd, Ian McKellen, Dominic Monaghan, Viggo Mortensen, Miranda Otto, John Rhys-Davies, Andy Serkis, Liv Tyler, and Karl Urban, plus writer Philippa Boyens and director Peter Jackson on May 31, 2020, joined Josh Gad's YouTube series Reunited Apart which reunites the cast of popular movies through video-conferencing, and promotes donations to non-profit charities.

"[85] On April 23, 2010, in a charitable gesture, Wood visited the Chilean town of Curepto, one of the hardest hit by the 8.8 magnitude earthquake that struck on February 27, 2010.

[89] During a 2016 interview with The Sunday Times, Wood accused Hollywood of being organized by pedophiles who preyed on children within the industry, including many of his fellow child actors.

[90] After the interview made international headlines, Wood clarified that he had "no firsthand experience or observation of the topic" and that his comments had been partly based on the documentary An Open Secret that he had seen.