Martin Henderson was born in Auckland, New Zealand. He began acting when he was thirteen, appearing in Strangers (1989), a local television production. He attended Westlake Boys High School and Birkenhead Primary. He first became a star in his home country, when he starred in the series, Shortland Street, playing the character Stuart Neilson from 1992 to 1995, in the early to mid 90s. He then moved to Australia to star in the short-lived soapie, Echo Point, and Sweat, which also starred a very young Heath Ledger. The pair became friends, and Martin convinced Heath to move to Sydney and make a go of his career, and the two lived together. Martin also worked on Home and Away, and Big Sky, as well as getting an AFI Award nomination for his supporting role in the Aussie film Kick. Martin left Australia to study acting and theatre in New York, where he also looked up Heath in LA.
Henderson spent more than a year unsuccessfully auditioning for film roles in Los Angeles, but in 2001, he was finally cast, in a supporting role in the John Woo-directed war film, Windtalkers. In 2002, he starred opposite actress Naomi Watts in the horror film, The Ring. In 2005, he starred opposite Indian actress Aishwarya Rai in the romantic film Bride & Prejudice, and in the award-winning Little Fish starring Cate Blanchett. In 2010, it was announced Henderson had been cast in the creator of Grey's Anatomy new television series Off the Map wherein doctors travel to the end of the world to rediscover why they had initially wanted to become doctors.
In 2018, he starred in the horror film The Strangers: Prey at Night (2018).