The game appeared steeped in controversy as Sundowns conceded a first half penalty and then had goalkeeper Dennis Onyango sent off in the second half.
The 2-0 win was enough to see Medeama into the group stages on the away goals rule, a good turnaround for the Ghanaians after they lost the first leg 3-1 in Tshwane.
Medeama striker Mohammed Abbas wasted a great chance to give his side the lead at the Essipong Stadium in the 30th minute, putting his effort wide from close range.
But in the 34th minute, Medeama were awarded a penalty for a foul by Thabo Nthethe inside the box. Malik Akowuah stepped up and fired home.
And Medeama put themselves ahead in the tie in the 65th minute as Bernard Ofori found the net. Just after that, Onyango was sent off for an apparent kick out at Abbas.
Medeama have thus qualified for the group stages of a Caf club competition for the first time while Sundowns will have to wait for the 2017 Caf Champions League for another shot at continental glory.