Spanning an impressive 13 feet in length, "Devolved Parliament" depicts the UK's House of Commons overrun with chimpanzees in a scene of mayhem.
The piece, which is the largest known canvas by the anonymous street artist, is expected to fetch between £1.5 million and £2 million (between $1.8 million and $2.5 million).
"Devolved Parliament" could therefore exceed Banksy's current auction record of £1.87 million, which was set in 2008 for "Keep It Spotless" at Sotheby's New York.
The satirical canvas was executed in 2009 for his groundbreaking "Banksy versus Bristol Museum" exhibition, which took place in his native Bristol and attracted more than 300,000 visitors.
At the time, Banksy famously said of the work, "You paint 100 chimpanzees and they still call you a guerrilla artist."
"Devolved Parliament" returned to the spotlight over the past few months, when its anonymous owner lent it to the Bristol Museum for a timely display marking both the 10th anniversary of "Banksy versus Bristol Museum" and the so-called Brexit Day on March 29.
Ahead of the exhibition, Banksy wrote on Instagram, "I made this 10 years ago. Bristol museum have just put it back on display to mark Brexit day. Laugh now, but one day no one will be in charge."
The last sentence refers to his 2002 "Laugh Now," in which a row of subservient apes bear the inscription "Laugh now, but one day we'll be in charge."
Although "Devolved Parliament" was not intended as a commentary on Brexit, the repeated deferral of Britain's exit from the European Union, now set on October 31, shed new light on the painting.
"Regardless of where you sit in the Brexit debate, there's no doubt that this work is more pertinent now than it has ever been, capturing unprecedented levels of political chaos and confirming Banksy as the satirical polemicist of our time," Alex Branczik, Sotheby's European head of contemporary art, said in a statement.
Banksy directly addressed Brexit in a mural on a building in Dover, which featured an overall-clad worker chiseling a golden star from the EU flag.
The artwork was mysteriously whitewashed on September 12, which prompted the street artist to write on Instagram, "Never mind. I guess a big white flag says it just as well."
Banksy also revealed that he planned to update the mural on October 31, depicting the EU flag crumpled on the ground while a worker keeps chipping away Britain's gold star.
"Devolved Parliament" will hit the auction block on October 3 in London as part of Sotheby's Contemporary Art Evening Auction.
The sale comes a year after Banksy famously installed a shredder in the frame of "Girl with Balloon," activating it moments after the artwork was sold for over £1 million.