Melissa George's first role came in the popular Australian TV soap Home and Away, where she appeared in 500 episodes from 1993. She left the soap in 1996 to move to Los Angeles to further her acting career.
George would go on to appear in Steven Soderbergh's crime thriller The Limey (1999), David Lynch's Mulholland Drive (2001) and the thriller Derailed(2005). She also landed roles in major TV series, including Alias and Hunted.
In 2007, George had a major role in the horror film 30 Days of Night, and she took the lead role in Triangle (2009). She also appeared in multiple episodes of the Apple TV+ series The Mosquito Coast opposite fellow Mulholland Drive actor Justin Theroux.