UFC president Dana White has since given the fight his blessing and intends to let MacDonald and Penn settle their differences Sept. 22 at UFC 152 in Toronto.
"We're going to do it," White said Friday night during the UFC on FX 3 postfight news conference in Sunrise, Fla.
MacDonald (12-1) is ranked No. 6 among welterweights by ESPN.com. His lone loss came in June 2010 against interim 170-pound champion Carlos Condit.
Since suffering the third-round TKO setback, MacDonald has won three consecutive fights.
Penn, who has held UFC title belts in both the lightweight and welterweight divisions, will make his first appearance since coming out on the short end of a lopsided unanimous decision Oct. 29 to Nick Diaz.
After that loss, Penn (16-8-2) hinted at retirement.
"This is probably the last time you'll see me in here," a heavily bruised Penn said. "I want to perform at the top level.
"I've got a daughter, another daughter on the way. I don't want to go home looking like this."
Several months later, however, Penn would inform White of his desire to fight again.
Dos Santos (15-1) claimed the heavyweight title from Velasquez with a first-round knockout in November 2011.
He defended the belt May 26 at UFC 146 with a second-round TKO of former champion Frank Mir.
Velasquez (10-1) earned a rematch with dos Santos by registering a first-round TKO of Antonio Silva in the UFC 146 co-main event.