Anthony Laffor, Yannick Zakri and Sibusiso Vilakazi were all on target as The Brazilians overpowered their Congolese counterparts in their own backyard.
Coach Pitso Mosimane rang the changes from their last outing – a league clash at home to Maritzburg United – with a number of players forced out through injury.
Denis Onyango, Thabo Nthethe, Lucky Mohomi, Laffor, Zakri and Vilakazi all came in to help Sundowns pass their test in Kinshasa.
Downs had the first real chance at goal in the ninth minute, when Zakri broke through the Vita defence with a good turn, but Nelson Lukong pulled off a great save to deny the striker from close range.
The visitors opened the scoring midway through the first half, with Laffor popping in unsighted at the backpost to head home Tebogo Langerman's excellent cross from the left flank.
The lead lasted just eight minutes though as Oumar Sidibe grabbed the eqauliser with a fine right-footed strike from outside the box catching Onyango out to his right.
Percy Tau was unlucky to have a decent penalty shout waved away by the referee, after he was clipped inside the Vita box en-route to a tantalising through-ball from Laffor in the 36th minute.
Zakri came agonisingly close to getting on the scoresheet on the stroke of half-time but was unlucky to be denied by the crossbar, after shrugging off two defenders.
Six minutes after the break, Sundowns could have taken the lead as Zakri picked out Tau inside the box but the latter's attempted lob was blocked by Lukong.
The Ivorian eventually got his goal just before the hour-mark as he profited off good defensive work by Themba Zwane, who stole the ball just outside the Vita box, before allowing Zakri to fire home with a first-time shot.
Zwane then had an excellent chance to extend the lead 10 minutes later as Tau broke away on a counter-attack down the left flank before picking out the former inside the area, but the midfielder's shot went over the bar with just the keeper to beat.
Vilakazi handed his side a two-goal cushion with under 15 minutes remaining, as he skipped past his marker before slotting home past Lukong with a low right-footed shot.
The win is Sundowns' first of the group stage campaign after being held to a goalless stalemate at home to Ethiopian side St. George, while the defeat leaves Vita rooted to the bottom of the group with two defeats from two games.
The defending champions next host Esperance in their third group clash next weekend.
AS Vita: Lukong, Baemeto, Ngonda, Obama, Kasereka, Munganga (Sugira 82'), Atuba, Ikanga, Etekiama, Sidibe, Mukoko.
Mamelodi Sundowns: Onyango, Nthethe, Madisha, Morena, Langerman, Mohomi, Vilakazi, T. Zwane (S. Zwane 85'), Laffor, (Castro 76') Tau, Zakri (Modise 71').
Unused subs: Sandilands, Hachi, Kekana, Ngcongca.