The victory for the defending champions means they open open up a three-point gap at the top of the table, although second-placed Orlando Pirates have two games in hand.
Sundowns head coach Miguel Cardoso made wholesale changes to his team from their CAF Champions League encounter against Al Hilal, with only Arthur Sales retaining his place.
The many changes led to a disjointed start to the contest from Sundowns, especially in the final third.
Iqraam Rayners had the first good opportunity but flashed his effort across the goal.
Sundowns were ramping up the pressure as Brayan Leon forced Sekhukhune goalkeeper Renaldo Leaner to a point-blank save.
Cardoso looked to his bench to find some inspiration and sent on Tashreeq Matthews and Nuno Santos to create a sparkle.
The move almost paid dividends but Matthews was denied by Leaner, who parried he forward's effort to safety.
Sundowns broke the deadlock in the first minute of injury-time when Khuliso Mudau did some good work down the right flank before finding Nuno Santos, who slotted in the bottom corner.
Leon the sealed the victory with header from a rebound after Leaner had initially denied Peter Shalulile.
Sekhukhune remain fifth in the standings following the defeat, three points behind second-placed Pirates, albeit having played three extra matches.
Sekhukhune United head coach Eric Tinkler admits his side was undone by the quality of the Mamelodi Sundowns substitutes in their 2-0 Betway Premiership defeat on Tuesday.
Miguel Cardoso has praised the club's fans for their support as Mamelodi Sundowns defeated Sekhukhune United 2-0 in the Betway Premiership.
Kaizer Chiefs will look to build on their recent run of form with all three points away to Marumo Gallants in the Betway Premiership on Wednesday night.
Kaizer Chiefs attacker Mfundo Vilakazi is confident his team can continue to get positive results ahead of the Betway Premiership clash against Marumo Gallants on Wednesday.
