The Pirates of the Caribbean star edged out Twilight's Robert Pattinson for Favourite Movie Actor a year after he was awarded the first Favourite Movie Actor of the Decade Award at the 2010 event.
Pattinson also missed out on the Favourite Male Star Under 25 Award - to Zac Efron.
Other early winners included Taylor Swift, who claimed the Favourite Country Artist honour and the Kardashians, who landed the Favourite TV Guilty Pleasure prize.
Neil Patrick Harris and Jane Lynch were named the Favourite TV Comedy Actor and Actress and Adam Sandler received the Favourite Comedic Star award from his Just Go With It co-star Jennifer Aniston.
House star Lisa Edelstein picked up the Favourite TV Drama Actress prize and the medical programme was honoured as Favourite TV Drama, while hit shows Hawaii Five-0 and William Shatner's $#*! My Dad Says were named Favourite New Drama and Favourite New TV Comedy. Glee was honoured as Favourite TV Comedy.
Queen Latifah hosted the show and was among the night's performers. Selena Gomez and Kid Rock also hit the stage.