UFC president Dana White confirmed the date and venue to ESPN.com on Monday, although sources say details are still being finalized.
The fight will headline a UFC pay-per-view event, expected to be UFC 166. The two split a pair of previous meetings. Dos Santos scored a first-round knockout in November 2011, Velasquez earned a decision victory in the rematch last December.
ESPN.com ranks Velasquez the No. 1 heavyweight in the world, with dos Santos at No. 2. With both men in their athletic prime, it's possible their rivalry could extend even beyond October.
Much of that, of course, will depend on how exactly the trilogy fight plays out.
"I think if Cain wins the fight as impressively as he did the last one, it'd be tough to do that fight again," White said.
Velasquez (12-1) first captured the UFC title with a dominant first-round victory over Brock Lesnar at UFC 121 in October 2010. He lost the belt in his first defense to dos Santos, but rebounded with a first-round victory over Antonio Silva.
The American Kickboxing Academy product has finished 10 of his 12 pro fights, all via knockout. He'll be seeking a second title defense in October.
Dos Santos (16-2) saw a 10-fight win streak snapped in the loss to Velasquez at UFC 155. He was out-struck 111 to 57 in the rematch, according to Fightmetric.com. The Brazilian bounced back with a third-round knockout over Mark Hunt in May.