In 2004, Worthington received Australia's highest film award for his lead performance in Somersault.

He performed predominantly in leading roles in a variety of low-budget films before moving to major studio films, ranging from romantic drama and comedy-drama to science fiction and action.

Worthington had a major role in Somersault (2004) and played the lead in a modern Australian retelling of Macbeth (2006). He won the AFI Award for Best Lead Actor for his role in Somersault. He was well known in Australia for his role as Howard in the acclaimed Australian TV series Love My Way, in which he played the main love interest of the female lead.

Worthington's international film career began with a series of small roles in Hollywood production The Great Raid (2005), which was filmed in Australia.

He auditioned for the role of James Bond in Casino Royale but lost the role to Daniel Craig.

He starred in the Australian creature-feature film Rogue (2007), as a man named Neil, which gained a 100% fresh rating from Rotten Tomatoes.

In Terminator Salvation, Worthington plays cyborg Marcus Wright who assists the humans despite their suspicions of him.

Shot prior to the release of Terminator Salvation, the James Cameron-directed science-fiction film Avatar was Worthington's next project.

In the film, he played Jake Sully, a paraplegic US Marine who, assigned to control an alien body called an avatar through a neural link, finds himself at the center of a war between his own species and the indigenous Na'vi people of the moon Pandora.

The film went on to become the highest-grossing film of all time, grossing more than US$2.730 billion ($3 billion adjusted for inflation) in box-office receipts worldwide.

In November 2010, Worthington told GQ Australia that he went to audition, but wasn't told what it was for and got annoyed. So he did his part, left, forgot about it — and was called back.

"I was a bit pissed off, and I think that came across," he says. "I think Jim saw a spark and liked it because that's Sully's character — a guy who doesn't like to be bullied and a guy who just wants to set things right."

He provided voice work for Captain Alex Mason, the protagonist character in the video game Call of Duty: Black Ops. Some gamers criticised Worthington's inability to mask his Australian accent, as in Avatar.

In November 2010 The Hollywood Reporter named Worthington as one of the young male actors who are "pushing – or being pushed" into taking over Hollywood as the new "A-List".

He was selected as one of the entrants to the Who's Who in Australia 2011 edition.

In November 2011, Worthington along with Jonah Hill and Dwight Howard starred in commercials for the video game Call of Duty: Modern Warfare 3.

In 2012, Worthington starred in the sequel to Clash of the Titans, called Wrath of the Titans, alongside Liam Neeson.

As in the first film, Worthington played the demigod and son of Zeus, Perseus. He also reprised his role as Alex Mason in Call of Duty: Black Ops II.

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