Merrells performed as Benedick in Much Ado About Nothing at the Liverpool Playhouse in 2007, and starred as Oedipus in another Berkoff production at the same venue in 2011. He was nominated for a Stage Award for Best Actor for that role. Later that year he played detective Philip Marlowe in The Big Sleep; The Stage said he was "charismatic" but "a touch too suave and slick".

In 2009, Merrells had a lead role in the 2009 film, Invisible Eyes. In 2010, he portrayed Ben Talbot, brother of Lawrence Talbot in remake of The Wolfman. In 2013, he portrayed the Roman commander Marcus Licinius Crassus in the Starz series Spartacus: War of the Damned. He had to undergo a strict diet and four-week fitness boot camp in preparation for the role, losing 21 lbs. Also that year, he portrayed character Mark Vega in the British horror film Judas Ghost. He also plays The Founder in the 2013 American remake of The Tomorrow People.

In 2014, Merrells starred in a small sci-fi film named Index Zero as Kurt, a main character, and two films in 2015, Billionaire Ransom (originally titled Take Down) and Victrix.

Also in 2015 Merrells starred in a Futuristic short film called The Leap as an enforcement agent whose job it is to stop people trafficking on an interplanetary scale.

In 2016, Merrells was cast as Tancrede de Hautville in the History channel's series Knightfall, which premiered in the United States in December 2017.