Sundowns kept the core of the side that thumped CR Belouizdad, with Peter Shalulile and Themba Zwane leading the fray up top and Sphelele Mkhulise a surprise inclusion.
Mazembe missed a big chance to take the lead on seven minutes from a cutback in the area that landed perfectly for Moustapha Kouyate, who shot straight at goalkeeper Denis Onyango.
The Ravens still controlled the tempo of the opening quarter with shots flying in from all angles whilst Masandawana struggled to get any foothold in the final third of the pitch.
As the pressure continued from the host, Sundowns threatened the lead with a low rasping shot on the centre of the area from Zwane but the opposite number parried onto the foot of the post.
Chances seemed to open up for the South Africans three minutes to halftime with a snap effort from the right-side by Gaston Sirino forcing a save off goalkeeper Ibrahim Mounkoro.
Mazembe made three changes upon the restart with Sudi Bibonge, Jean Othos and Miche Mika introduced whilst the Brazilians remained unchanged.
The Brazilians dusted off their slow spell from the first stanza with questions of their own through Lebohang Maboe and Thapelo Morena, but Mounkoro saved.
Masandawana were rewarded for their upward momentum midway in the second half after Shalulile finished off a perfect ball in the area from Zwane.
This urged Mazembe forward and within the last five minutes, levelled through a smart finish from Tresor Mputu after Sundowns failed to clear their lines.
Masandawana though had the final say at the death when a free-kick from Lyle Lakay gave Mounkoro no chance for his side's first victory at Mazembe.
Sundowns: Onyango, Nascimento, Lebusa, Lakay, Coetzee, Morena, Mkhulise, Maboe, Sirino, Zwane, Shalulile.
Subs: Mweene, Erasmus, Jali, Mvala, Kapinga, Modiba, De Reuck.