He played supporting roles in the Dutch films Costa! and Volle Maan, both of which were directed by Johan Nijenhuis and aimed at a teen-aged audience. At the same time, he also had a recurring role on the Dutch police series Spangen. Huisman moved into leading-man territory in 2003 with the film Phileine Says Sorry, which was an adaptation of Ronald Giphart’s book of the same title. He also starred as medieval knight Floris in the film Floris, based on the Dutch TV series.

In the years that followed he played a leading role in the football comedy Johan, recurring guest roles in the comedy series Meiden van De Wit and the first season of the drama series Bloedverwanten, and the leading role in the medical drama series De Co-Assistent. He also played a small supporting role in the 2006 film Zwartboek by Paul Verhoeven, which became the most successful Dutch film of all time.

In 2006, Huisman made his first foray into the international acting world with a supporting role in an episode of the British TV series Dalziel and Pascoe. He followed this with a role as Ernest II, Duke of Saxe-Coburg and Gotha in The Young Victoria, and the BBC made-for-TV drama Margot in which he portrayed Rudolf Nureyev. He then joined the main cast of the HBO series Treme, as Sonny, a Dutch busker who plays keyboards and guitar. He was taught New Orleans piano by Davis Rogan. During his time on Treme, Huisman also played a small supporting role in the apocalyptic action film World War Z and started recurring as Liam McGuinnis on Nashville.

Huisman is married to Dutch actress Tara Elders, and they have a daughter who was born in 2007. The couple formerly lived in New Orleans, Louisiana; and now reside in New York City.

In 2014, Huisman appeared in the Academy Award-nominated biographical drama film Wild and starred in the advertising campaign for Chanel No.5’s The One That I Want, which was directed by Baz Luhrmann. In 2015, Huisman co-starred in the thriller The Invitation, and played the leading role in the fantasy romance film The Age of Adaline.

In 2016, Huisman was cast as the lead role in the war-drama The Ottoman Lieutenant which tells the story of a Turkish officer (Huisman) who falls in love with an idealistic American nurse, played by Hera Hilmar, during World War I. The film also stars Josh Hartnett and Ben Kingsley. The film was released for an Oscar-qualifying run in December 2016 before wide release in March 2017.

Also in 2016, Huisman played Walter Davidson in the Discovery Channel limited series Harley and the Davidsons which told the origin story of Harley-Davidson Inc. The three-part series premiered in September 2016 and gained reasonable reviews from critics and from Harley-Davidson themselves.

Huisman starred in the thriller film 2:22 which was released on 30 June 2017. That year, Huisman was cast as Sam, the male lead in the romantic drama Irreplaceable You. The film co-starred Gugu Mbatha-Raw as his childhood sweetheart, and later fiancée, who is diagnosed with terminal cancer, and Steve Coogan and Christopher Walken also appear. The film was released on 16 February 2018 on Netflix and has a Rotten Tomatoes rating of 33% Fresh. Also in 2018, Huisman starred opposite Lily James as Dawsey Adams, the male lead in the romantic drama The Guernsey Literary and Potato Peel Pie Society, based on the 2008 novel of the same name.

In 2018, Huisman starred in the Netflix horror series The Haunting of Hill House, which is based on Shirley Jackson’s 1959 novel of the same name. The 10-episode drama, released on 12 October 2018, is a modern re-imagining of the original story, now about a family of seven. Huisman plays Steven Crain, the oldest sibling, who becomes a published writer of supernatural books, including a memoir about his family’s time living at Hill House. Mike Flanagan wrote, directed and executive-produced the series. In 2019, Huisman had a lead role in the Netflix film The Red Sea Diving Resort, as an Israeli agent.