Lee, 63, was in no mood to celebrate as he accepted an honorary award presented by Martin Scorsese at the virtual awards show.
The "Da 5 Bloods" director filmed his speech on Jan. 6, "a very sad day in the history of America," when pro-Trump rioters stormed the U.S. Capitol building.
"You know what, we are living in a very serious time in America. All of us as true Americans have to really think about what’s important," said Lee. "There’s no way possible to go before the iPhone and thank you guys without telling you what’s in my heart and soul as a descendent of slaves who helped build this country.
"The whole world is laughing at the United States, the so-called cradle of democracy," he added.
"We’re at the crossroads now. And everyone please be safe, this is not a game. These people got guns with ammunition," said Lee. "This president, President Agent Orange, will go down in history with the likes of Hitler. These guys, all his boys, they are going down on the wrong side of history."
Lee, a frequent critic of Trump, then gave thanks for the award given for his pandemic-era short film "New York, New York."
Chadwick Boseman was honored as best supporting actor for Lee's "Da 5 Bloods." Boseman's widow, Simone Ledward Boseman, accepted the award on her late husband's behalf.
"He would have thanked God, first and foremost, his mother and his father," she said. "Chad was a New York actor. He knew the New York hustle. So he was unfazed by much when he got to Hollywood because in New York he was at war."
"Da 5 Bloods" co-star Norm Lewis presented the award for Boseman, who died last August of colon cancer, saying, "He'll forever be remembered for his versatility and his immense talent."
More: The award winners
Delroy Lindo took best actor for his role as conflicted Vietnam veteran Paul in "Da 5 Bloods," which was presented by his "Crooklyn" co-star Alfre Woodard.
"He brings us right to the tortured heart of Paul," said Woodard of Lindo's performance. "Delroy, you have given young actors and experienced actors a template in Paul. This is how you do."
Lindo praised his director Lee. "Anybody who has followed Spike's work over the last 35 years knows he has not only inspired generations of filmmakers but filmgoers globally."
Bulgarian actress Maria Bakalova, the 24-year-old star of "Borat Subsequent Moviefilm," received best supporting actress, saying the award was an inspiration for Bulgarian actors that "things like this can happen."
Frances McDormand presented best director to her "Nomadland" director Chloe Zhao, saying "it was one she most deeply deserves." During her acceptance speech, Zhao said it was at New York University where she "learned how to take my first steps as a filmmaker."
Best film went to "First Cow," presented by "Parasite" director Bong Joon-ho, who said he is "often awed" by director Kelly Reichardt, calling the film "a unique story" and "a story only Kelly could make."
This article originally appeared on USA TODAY: Spike Lee speech: Donald Trump belongs with 'the likes of Hitler'