UFC officials confirmed the matchup on Wednesday, after an initial report by the Edmonton Sun. The UFC 215 pay-per-view will take place at Rogers Arena.
Dos Santos (18-5) is 33 and at something of a crossroads coming off a first-round TKO loss to defending champion Stipe Miocic in May.
The Brazilian has a 4-4 record in his past eight contests, including three losses via knockout. He was also limited to just one appearance in 2014, 2015 and 2016 because of injuries.
Ngannou (10-1) is one of the hottest fighters in the division, with wins in his past nine fights overall. He signed with the UFC in 2015 and has recorded finishes in all five of his appearances.
Originally from France now fighting out of Las Vegas, Ngannou, 30, is coming off a first-round TKO win over Andrei Arlovski in January.