Nicholls made his TV debut in 1989, at the age of 10, in Children's Ward. In 1994 he appeared in the BBC children's drama Earthfasts and The Biz, a teenage performing arts drama filmed at Hampton Court.
Nicholls character of Joe Wicks in BBC's EastEnders earned him national attention.
In his late teenage years he appeared in many popular culture magazines including Attitude, BIG!, Bliss, Gay Times, Heat, Just Seventeen, Live & Kicking, MIZZ, My Guy, Now, OK, Radio Times, Shout, Sky International, Sky magazine, Smash Hits, Sneak, Sugar, TV Hits, TV Times, and What's on TV.
Nicholls appeared in several teenage stage roles, notably as Aladdin in Aladdin - Genie of the Ring at the Central Theatre in Chatham (1996/97) and as Billy Fisher in the 1998 production of Billy Liar at the Bush Theatre in Shepherd's Bush.
Nicholls played PC Terry Sydenham in the police series City Central from 1998 to 1999; and also in 1999 played Christ in the 3-part BBC contemporary Easter production of The Passion. His West End debut was in 2000 as Edmund Tyrone in Eugene O'Neill's Long Day's Journey into Night at the Lyric. Other London stage appearances include Mrs Steinberg and the Byker Boy at the Bush Theatre (2000).
Nicholls' film appearances include World War I drama The Trench in 1999. In 2001 he played Charlie in Goodbye Charlie Bright. He went back to the stage in 2002 playing Vincent in Brixton at the Royal National Theatre. In 2003 he appeared in the BBC adaptations of The Canterbury Tales (The Wife of Bath). He also appeared in the final episode in series 3 of Hustle. He appeared in the 2004 6-part BBC miniseries Gunpowder, Treason & Plot and in Festen in 2005.
Other roles include If Only and a cameo role in Bridget Jones: The Edge of Reason. He appeared briefly as a street boxer in Nick Love's 1999 short film Love Story.
In July 2007, he played the part of Terry in Channel 4's Clapham Junction. This drama depicted 36 hours in the life of several gay men and was filmed to commemorate the 40th anniversary of the legalization of homosexuality in England and Wales. Also in 2007 he played Connor Gruff in the 'Billy Goat' episode of the BBC series Fairy Tales.
Nicholls' 2008 career began as the character Robert Fielding in Harley Street alongside Suranne Jones. He also played Harry Keegan in Secret Diary of a Call Girl alongside Billie Piper, Judas in another BBC Easter series entitled The Passion, and appeared in A Thing Called Love.
He appears in the 2012 UK feature film Life Just Is opposite Jayne Wisener.
Nicholls also appeared as Simon Marshall in BBC1's hospital drama serial Holby City between May and July 2012, and played Cal Beckett in Channel 4's new crime thriller, The Fear. He played the role of DS Sam Casey in ITV's Law & Order: UK until the end of series 7 in 2013.
Nicholls married his girlfriend Chantal Brown in 2008 at Hampstead, north London. They divorced in 2015.
In July 2017, Nicholls was badly injured while on holiday in Thailand after falling from a waterfall in Ko Samui. As his mobile phone was broken, he was left stranded at the bottom of the waterfall for three days, and only rescued by volunteer rescuers, police and medics after locals alerted police to the motorcycle he had travelled on, which lay abandoned nearby. He was later taken to hospital, suffering from two broken legs and a shattered knee. Nicholls' agent said he was "recovering well".
Nicholls is a supporter of Bolton Wanderers Football Club and his interests include skateboarding, kickboxing, basketball and surfing in Newquay, Cornwall.