No matter what the character is, I just say to myself 'If I, Melissa George, was in that situation, how would I react?' and once you do that you can just go for it, and hopefully the performance comes through.

After moving to America Melissa George appeared in television series such as Friends (2003) Alias (2003–2004) In Treatment (2008) Grey's Anatomy (2008–2009) and Lie to Me (2010) earning a nomination for a Golden Globe Award for Best Supporting Actress – Series Miniseries or Television Film for In Treatment. On 9 November 2009 it was announced that George would guest-star in at least two episodes of Fox's Lie to Me playing Clara Martin. In November 2010 George was named the new face of L'Oreal Melbourne Fashion Festival.

George is perhaps best known in Australia for her role as Angel Parrish on the Australian soap opera Home and Away (1993–1996). She made her film début in the neo-noir science fiction feature Dark City (1998) and later appeared in supporting roles in films including The Limey (1999) and Mulholland Drive (2001).