And Colin Farrell was named best actor for his part in the pitch-black Irish drama "The Banshees of Inisherin", which also won the best screenplay award for writer-director Martin McDonagh.
But the jury, led by Julianne Moore, determined that the best of the 23 films in competition was "All the Beauty and the Bloodshed".
It is the latest documentary from Oscar-winner Laura Poitras, who previously made history as the first contact with whistleblower Edward Snowden when he exposed massive surveillance by the National Security Agency.
Her new film explores the traumatic and brilliant life of photographer Nan Goldin, and her recent campaign to publicly shame the Sackler family who own the pharmaceutical firm behind painkiller Oxycontin.
"I've known a lot of brave and courageous people in my life but I've never known anyone like Nan," Poitras said as she picked up the award.
"Someone who could decide to take on the billionaire Sackler family, which is ruthless and responsible for countless deaths and so much bloodshed."
The opioid addiction crisis has caused more than 500,000 overdose deaths in the United States, and the Sackler's company has been ordered to pay up to US$6 billion in damages.
Taylor Russell won the best newcomer award for "Bones and All" in which she played alongside Timothee Chalamet as lovelorn cannibals.
Italy's Luca Guadagnino also won best director for the film, which saw him reunited with Chalamet following their Oscar-nominated "Call Me By Your Name".
The Special Jury prize went to "No Bears" by Iran's Jafar Panahi who in July was imprisoned for "propaganda against the system". His detention was the subject of a flash-mob protest Friday on the Venice red carpet, led by Moore.
The film's actor, Reza Heydari, told journalists after the awards he had received a message earlier in the day from Panahi in prison.
"He told me do not get in trouble for him," he said. "The award he has received brings a message -- an artist in a prison or outside a prison can still produce his message because he loves art and he loves cinema."
The second place Silver Lion went to "Saint Omer" by French director Alice Diop, inspired by the true story of a Senegalese migrant on trial for infanticide in France.
Critics were deeply divided over many of the films at this year's festival, but it was a stellar year for individual actors.
There were rave reviews for Brendan Fraser, making an unlikely comeback from the Hollywood wilderness as a morbidly obese English professor in "The Whale".
And Hugh Jackman's performance as a father dealing with a depressed teenager in "The Son" was labelled the best of his career.
Netflix had been hoping for a big year, but its much-hyped Marilyn Monroe biopic, "Blonde", tested the patience of many critics, despite acclaim for its Cuban star Ana de Armas.