UFC officials announced Wednesday both fighters have verbally agreed to the matchup. The event takes place at Air Canada Centre in Toronto on Dec. 10.
The two first fought at UFC 92 in December 2008 for the interim heavyweight title.
Mir came away with a second-round TKO victory, becoming the first man to ever finish Nogueira in his storied career. After the bout, it was revealed the Brazilian had dealt with a staph infection and knee injury during the fight.
Mir (15-5) went on to lose to Brock Lesnar at UFC 100 in a bid to capture the undisputed heavyweight title. Since the loss, the Las Vegas native has gone 3-1, including two finishes via knockout.
In May, Mir cruised to a unanimous decision over Roy Nelson in the co-main event at UFC 130.
Nogueira (33-6-1) looks to build on a major upset win over Brendan Schaub last month at UFC 134 after he seemed destined for retirement.
Following a first-round knockout loss to current champion Cain Velasquez in February 2010, Nogueira was sidelined for 18 months due to knee and hip surgeries.
The 35-year-old turned back the clock in a first-round knockout over Schaub, however, setting the stage to prove he wasn't at his best in the first fight against Mir.
Brett Okamoto covers mixed martial arts for ESPN.com. Follow him on Twitter.