A story of a lonely, washed out fighter won the Golden Lion for best film at the Venice festival on Saturday.
Directed by Darren Aronofsky, The Wrestler stars Hollywood outsider Mickey Rourke in an echo of his own troubled life in and out of the boxing ring and film studio.
Aronofsky previously made Pi and Requiem for a Dream.
Rourke, 51, described it as the best and the hardest film he has ever made.
Jury president, German director Wim Wenders, said the award was for "a film with a truly heartbreaking performance...."
The Silver Lion for best director was won by Alexei German Jr. of Russia for Paper Soldier, set on the barren steppes of Kazakhstan and centring around the Soviet space programme of the 1960s.
Best actor award went to Silvio Orlando of Italy for his role in Il Papa di Giovanna (Giovanna's Father), a story of an overprotective father and his mentally deranged daughter.
Best actress prize was won by Dominique Blanc in L'Autre (The Other One), a haunting tale of a woman who becomes dangerously obsessed with a young ex-boyfriend.
Teza, by director Haile Gerima of Ethiopia, received two prizes: the special jury award and best screenplay.
The story chronicles the life of an Ethiopian intellectual who flees his country during the Marxist "red terror" in the 1980s, only to be viciously attacked in Germany by racist youths.
US actress Jennifer Lawrence was named best emerging actress for her role in The Burning Plain, in which she appears alongside Oscar winners Kim Basinger and Charlize Theron in a story directed by Guillermo Arriaga of Mexico.
The Hurt Locker by US director Kathryn Bigelow led an informal poll of Italian critics.
Actress Anne Hathaway also impressed for an unusually dark role in Rachel Getting Married," directed by Jonathan Demme.