The 3D leviathan, which is rapidly racing up the highest grossing box office charts, saw Cameron repeat the Golden Globe success he had with Titanic, which went on to win big at the Oscars.
Accepting the direction award, Cameron paid tribute to his ex-wife Kathryn Bigelow, who was also nominated for helming bomb disposal team drama The Hurt Locker.
"Frankly, I thought Kathryn was going to get this. She richly deserves it," he said.
The Hangover was named best comedy/musical, while Meryl Streep and Robert Downey Jnr took home the acting honours for comedy/musicals for their roles in Julie & Julia and Sherlock Holmes.
But it was a disappointing night for the British film establishment, especially after last year's Slumdog Millionnaire triumph. Helen Mirren (The Last Station), Carey Mulligan (An Education) and Emily Blunt (The Young Victoria) were all in the running for best actress in a drama, but lost out to Sandra Bullock for her performance in heartstring-tugger Blind Side.
Colin Firth also had to go home empty-handed for his role as a gay man grieving for his dead partner in A Single Man, losing out in the drama acting category to Jeff Bridges, for his role in country music flick Crazy Heart.
Completing the acting gongs were Mo'Nique and Christoph Waltz who had been hotly tipped to scoop their supporting actor awards for their roles in Precious and Inglourious Basterds.
Accepting his award, Austrian Waltz said: "A year and a half ago I was exposed to the gravitational forces of Quentin Tarantino.
"He took my modest little world, my globe, and with the power of his talent and his words and his vision, he flung it into its orbit, a dizzying experience."
Pixar's Up, meanwhile, was named best animation, while Jason Reitman's Up In The Air took home only one prize - for best screenplay - despite receiving the most nominations. Michael Haneke completed a great night for Austria, by scooping yet another award for The White Ribbon, named best foreign language film.
Perhaps the most deserving moment of the night, however, was when Martin Scorsese received the Cecil B DeMille lifetime achievement award.
His long-time friend and collaborator Robert De Niro, who joked that the pair have spent the last decade presenting each other with awards.
He said: "We're like an old married couple. We built a life together, we have great memories - we just don't sleep together any more."
The full list of winners and nominees is below, for Golden Globe TV winners, visit the official site\ Full nominations are below:
Best Motion Picture - Drama
Winner: Avatar
The Hurt Locker
Inglourious Basterds
Precious: Based On The Novel Push By Sapphire
Up In The Air
Best Performance By An Actress In A Motion Picture - Drama
Emily Blunt - The Young Victoria
Winner: Sandra Bullock - The Blind Side
Helen Mirren - The Last Station
Carey Mulligan - An Education
Gabourey Sidibe - Precious: Based On The Novel
Push By Sapphire
Best Performance By An Actor In A Motion Picture - Drama
Winner: Jeff Bridges - Crazy Heart
George Clooney - Up In The Air
Colin Firth - A Single Man
Morgan Freeman - Invictus
Tobey Maguire - Brothers
Best Motion Picture - Comedy Or Musical
(500) Days Of Summer
Winner: The Hangover
It's Complicated
Julie & Julia
Nine
Best Performance By An Actress In A Motion Picture - Comedy Or
Musical
Sandra Bullock - The Proposal
Marion Cotillard - Nine
Julia Roberts - Duplicity
Meryl Streep - It's Complicated
Winner: Meryl Streep - Julie & Julia
Best Performance By An Actor In A Motion Picture - Comedy
Or Musical
Matt Damon - The Informant!
Daniel Day-Lewis - Nine
Winner: Robert Downey Jr. - Sherlock Holmes
Joseph Gordon-Levitt - (500) Days Of Summer
Michael Stuhlbarg - A Serious Man
Best Animated Feature Film
Cloudy With A Chance Of Meatballs
Coraline
Fantastic Mr Fox
The Princess And The Frog
Winner: Up
Best Foreign Language Film
Baaria (Italy)
Broken Embraces (Spain)
The Maid (La Nana)(Chile)
A Prophet (Un Prophete)(France)
Winner: The White Ribbon
(Das Weisse Band - Eine Deutsche Kindergeschichte)(Germany)
Best Performance By An Actress In A Supporting Role In A
Motion Picture
Penelope Cruz - Nine
Vera Farmiga - Up In The Air
Anna Kendrick - Up In The Air
Winner: Mo'Nique - Precious: Based On The Novel
Push By Sapphire
Julianne Moore - A Single Man
Best Performance By An Actor In A Supporting Role In A
Motion Picture
Matt Damon - Invictus
Woody Harrelson - The Messenger
Christopher Plummer - The Last Station
Stanley Tucci - The Lovely Bones
Winner: Christoph Waltz - Inglourious Basterds
Best Director - Motion Picture
Kathryn Bigelow - The Hurt Locker
Winner: James Cameron - Avatar
Clint Eastwood - Invictus
Jason Reitman - Up In The Air
Quentin Tarantino - Inglourious Basterds
Best Screenplay - Motion Picture
Neill Blomkamp - District 9
Mark Boal - The Hurt Locker
Nancy Meyers - It's Complicated
Winner: Jason Reitman - Up In The Air
Quentin Tarantino - Inglourious Basterds
Best Original Score - Motion Picture
Winner: Michael Giacchino - Up
Marvin Hamlisch - The Informant!
James Horner - Avatar
Abel Korzeniowski - A Single Man
Karen O,
Carter Burwell - Where The Wild Things Are
Best Original Song - Motion Picture
Cinema Italiano - Nine -
Music & Lyrics By: Maury Yeston
I Want To Come Home - Everybody's Fine -
Music & Lyrics By: Paul Mccartney
I Will See You - Avatar -
Music By: James Horner, Simon Franglen;
Lyrics By: James Horner, Simon Franglen, Kuk Harrell
Winner: The Weary Kind (Theme From Crazy Heart) - Crazy
Heart -
Music & Lyrics By: Ryan Bingham, T Bone Burnett
Winter - Brothers - Music By: U2; Lyrics By: Bono
