Star Wars - Lord of the Rings - X-Men

Although Monaghan held many occupations when he was younger, he always wanted to be an actor. After his second year at St. Anne's, Monaghan became a regular in school plays such as Oliver Twist, A Christmas Carol and Bugsy Malone before joining the Manchester Youth Theatre. There, he was scouted for Hetty Wainthropp Investigates, on which he played Hetty's under-aged sidekick, Geoffrey Shawcross, for four series. He made his feature-film debut as Russian sailor Sasha in the TV film Hostile Waters.

Monaghan later starred in The Lord of the Rings film trilogy as Meriadoc Brandybuck, for which he achieved international acclaim and success. Monaghan narrated Ringers: Lord of the Fans, a documentary about The Lord of the Rings fandom. He also provided the narration for The Discovery Channel's documentary Devil's Bible in 2008. He also appeared in Soldiers of Fortune alongside Sean Bean and Christian Slater. He was a regular cast member on the ABC series Lost from 2004 to 2007, playing English ex-rockstar and drug addict Charlie Pace. Monaghan originally auditioned for the role of Sawyer. The role of Charlie was then changed from an old, washed up rocker from the 1980s to a young one-hit wonder to accommodate Monaghan's age. Monaghan returned to the series as a special guest star after departing from the main cast.

In 2009, Monaghan starred as Chris Bradley / Bolt in X-Men Origins: Wolverine. On 15 July 2009, it was confirmed that he would join the cast of ABC Studios' science fiction television series FlashForward as the character Simon. The series premiered on 24 September 2009. It was canceled after its first season.

On 18 March 2010, Monaghan was spotted at the Universal Sheraton filming a short called Gloria. It was part of a programme called REESES Puff's Extraordinary Cinema (where the teens replace the pros). He played the part of Caleb Reese.

In 2010, Monaghan and Megan Fox made an appearance as a couple in an abusive relationship in the music video for rapper Eminem's song "Love the Way You Lie". Scenes include the celebrities on top of a liquor store. Fox and Monaghan also filmed inside the store and "at a seedy dive bar next door" to the store.

In November 2012, a new show on Channel 5 titled Wild Things with Dominic Monaghan began airing in the UK. The documentary shows Monaghan traveling to various locations such as Venezuela and Ecuador to film and interact with the exotic and often dangerous local wildlife.

During the summer of 2013, Monaghan appeared in several live-action teasers for 2K Marin's science fiction video game "The Bureau: XCOM Declassified".

Monaghan is a fan of The Gaffer Tapes: Fantasy Football Podcast and has appeared as a guest in both April and November 2016 and May 2018, as well as submitting several audio questions which are played on the podcast. While appearing as a guest, Monaghan stated: "It's the best fantasy football podcast out there".

Monaghan is a contributing writer for the music and culture magazine Paste, primarily writing articles about Premier League football.

Monaghan is the voice of Sightseeing Manchester's bus tour, recorded in March 2016.

Since August 2018 he has been starring as a serial killer in Channel 9 Australia's Murder Mystery Drama show Bite Club, which is filmed in and around Sydney.