His professional acting career began in 1999, with a role on the popular Australian soap opera Neighbours. 

His television career was later followed by roles in Child Star: The Shirley Temple Story, Blue Heelers, Something in the Air and The Saddle Club.  In 2002, Nathan made his feature film debut with the lead in Australian Rules, earned him a nomination for the Film Critics Circle of Australia's Best Actor award, alongside David Gulpilil, Guy Pearce and Vince Colosimo.  Phillips's film career has seen him star in both Australian productions, such as Take Away (with Rose Byrne), One Perfect Day (with Abbie Cornish), Balibo with Oscar Issac, and Under the Radar, and Hollywood productions such as Chernobyl Diaries, Redline and Surfer, Dude and most notably Snakes on a Plane. 

He is perhaps most known for his role as backpacker Ben Mitchell in the 2005 hit horror film Wolf Creek. After the success of this film, Phillips moved to Los Angeles, where he was based for several years. Worked on FX show The Bridge opposite Diane Kruger. He then won awards and raving reviews for the Post Apocalyptic Australian thriller, These Final Hours as the lead with Angourie Rice, Jess Degouw and Sarah Snook in 2015. Since then he has been acting and producing films like Blood Vessel, Thirteen Summers, Kid Snow, Halifax, NCIS Sydney, Kane and most recently Homeward.