The film marks Fraser's first leading role in around a decade, continuing his comeback after last year's Steven Soderbergh thriller No Sudden Move.
Adapted for film by Samuel D. Hunter from his own award-winning play of the same name, The Whale follows Fraser as a 42-stone man living as a social recluse.
His life changes when the opportunity arises to reconnect with his estranged 17-year-old daughter, played by Stranger Things star Sadie Sink.
A24 announced this week that The Whale will be one of three of its projects to have its world premiere at the Venice Film Festival, alongside Joanna Hogg's The Eternal Daughter and Pearl — Ti West's prequel to this year's horror hit X.
The film is Aronofsky's first directorial outing since his controversial 2017 film mother!, which starred Jennifer Lawrence as a woman descending into a nightmare due to unwanted house guests.
Fraser has described The Whale as "like something you haven't seen before" and teased his prosthetic-aided transformation in an interview with Unilad.
He said: "The wardrobe and costume was extensive, seamless, cumbersome. This is certainly far removed from anything I’ve ever done but not to be coy... I do know it’s going to make a lasting impression.”
Hunter told Deadline when the project was announced that it had been a "labour of love" to transpose his work from the stage to the screen.
He added: "This story is deeply personal and I'm very thankful it will have the chance to reach a wider audience.
"I've been a fan of Darren's ever since I saw Requiem for a Dream when I was a college freshman writing my first plays, and I'm so grateful that he's bringing his singular talent and vision to this film."
Fraser's big screen renaissance is set to continue, with a role in Martin Scorsese's crime tale Killers of the Flower Moon in the can.
He is also set to play pyromaniac supervillain Firefly in DC superhero movie Batgirl, directed by Bad Boys for Life and Ms. Marvel duo Adil El Arbi and Bilall Fallah.
Fraser carved out a lucrative career as a Hollywood heartthrob in the 1990s, most notably with lead roles in movies like The Mummy and George of the Jungle.
His career stalled during the 2010s and he only worked sporadically before returning to major movies with Soderbergh's No Sudden Move, in which he played a mob recruiter.
In 2018, Fraser claimed he was touched inappropriately in 2003 by Philip Berk — former president of the Hollywood Foreign Press Association, the organisation behind the Golden Globes.
In response to the allegation, which Fraser did raise to the organisation at the time, the HFPA said: "We want to reiterate that the HFPA understands today — as it did 15 years ago — that what Mr. Fraser experienced was inappropriate."
The Whale has not yet been scheduled for a UK release.
Watch: Brendan Fraser gets emotional about internet support