Friend was born and brought up in Stonesfield, Oxfordshire, the son of Caroline, a solicitor, and Nicholas Friend, a cultural historian. He attended Marlborough School in Woodstock. He moved to take A-levels at the Cherwell School and d'Overbroeck's College in Oxford. Friend received his professional acting training at the Webber Douglas Academy of Dramatic Art in London. He considered himself a late starter: "I was about to set off sailing around the world when I heard I'd got into drama school. Everyone else there had grown up singing and dancing, whereas I was the opposite."
Originally he wanted to be an archaeologist and travel around the world after seeing Indiana Jones and the Last Crusade in 1989, but he scrapped the idea after realizing that the occupation is not as remunerative as he had expected. Instead, he turned to acting, in which he was also inspired by Harrison Ford, who played Indiana Jones, and Marlon Brando who played Vito Corleone.
He played three minor roles in the film The Laramie Project when he was in second year in his drama school, and was spotted by the film's casting director, who eventually introduced Friend to a larger role. He made his acting debut as Billy Downs in the 2004 film The Libertine from The Weinstein Company, for which he was named "outstanding new talent" at the 2005 Satellite Awards. In 2005, he had his first starring role as Ludovic Meyer in the film adaption of Mrs Palfrey at the Claremont, in which he starred opposite Joan Plowright. In the same year, he portrayed Wickham in Joe Wright's version of Pride and Prejudice. In 2008, Friend and Tom Mison wrote and starred in a short film called The Continuing and Lamentable Saga of the Suicide Brothers. He founded his own production company called Beat Pictures, and he made his directorial debut with a short film in 2010 called Steve, which starred Keira Knightley, Tom Mison and Colin Firth. In addition to directing, he wrote and produced the film, which was later included in the 2012 compilation Stars in Shorts.
He also starred in the film Chéri and played the titular character. In addition, he joined the cast of The Boy in the Striped Pyjamas and played Kurt Kotler, a Lieutenant in Nazi Germany. In 2010, he played Albert, Prince Consort in Young Victoria. Graham King, producer of Young Victoria, chose Friend to star in the lead role because he remembered Friend's strong performance in Pride and Prejudice. His performance received acclaim, in particular, from historian Alex von Tunzelmann, who praised him for putting in effort in mastering the role.
In 2010, Friend made his stage debut as Mitchell in the UK premiere of The Little Dog Laughed. He stars in the films The Kid, based on the novel by Kevin Lewis. As the film involves boxing, he had to train himself so as to improve his physical and psychological shape. He also starred in a French film called Lullaby for Pi, playing a singer called Sam. In 2011, he played Thomas Anders, the protagonist of the film 5 Days of War.
In 2014, Friend played Oliver Baumer in Fox Searchlight's film Starred Up. His performance was applauded by critics and was nominated for BIFA Award for Best Supporting Actor. In 2015, Friend starred as Agent 47 in Hitman: Agent 47, a film based on the Hitman video game franchise, replacing Paul Walker. In order to play the role, he had to shave all his hair. The production team also sent him copies of all the Hitman games for him to familiarize himself with the character.
He played a major role as Peter Quinn in the multiple award winning political thriller series Homeland. Introduced in season two as a minor supporting character, his role became significantly larger after season three. His performance received acclaim and he was nominated for three different awards. Friend reprised his role as Quinn in the fifth season of Homeland, which was filmed entirely in Berlin, Germany and premiered on 4 October 2015.
In an interview on BBC Radio 4's The Film Programme, James Bond casting director Debbie McWilliams stated that Friend was asked if he'd like to be considered for the role of James Bond but turned it down.
From 2005 to 2010, Friend dated English actress Keira Knightley, whom he met when filming Pride & Prejudice. He began dating American athlete and actress Aimee Mullins in 2013, and they became engaged in December 2014. Friend and Mullins were married on 1 May 2016.