Lebohang Maboe opened the scoring with a thunderous strike from outside the box, before Lyle Lakay put the game to bed with a left-footed strike in the first half.
SuperSport United tried to launch a comeback after the restart, but it wasn't to be as Sundowns claimed the bragging rights in the Tshwane Derby even with Morgan Gould pulling one back midway through the second half.
Things could have been different though had the home side not hit the woodwork 10 minutes after the restart through Aubrey Modiba's right-footed shot.
Mosimane made several changes to his usual starting line-up as he looked to extend his unbeaten run against Matsatsantsa to 14 league matches.
It was also encouraging to see Rivaldo Coetzee in the starting line-up for the defending champions.
Coetzee's career took a nosedive when he first joined the Tshwane giants carrying a foot injury, but the technical team, especially Mosimane, has been very patient with the South Africa international.
For SuperSport, this clash was always going to be difficult without some of their star players including Dean Furman, Clayton Daniels, Bradley Grobler and Thuso Phala, who all had to watch from the stands.
After a frantic start to the game, Sundowns took full control of the encounter as they crowded the midfield and used their full-backs to penetrate their nemesis' back four.
Reneilwe Letsholonyane and Phumlani Ntshangase didn't quite click in midfield as they struggled to put a string of passes together, and it was for this reason that Kaitano Tembo saw the need to withdraw the Bidvest Wits loanee in the first half.
But the damage was already done even before Ntshangase went off, but perhaps the dimunitive midfielder had to be substituted as he had a hand in Sundowns' opening goal.
Maboe raced through the middle with Ntshangase closely monitoring him, before turning him inside out to set himself up for a shot which left Ronwen Williams stranded.
A comedy of errors inside the Matsatsantsa box allowed Lakay to double Sundowns' lead in similar fashion, beating Williams hands down with a low shot.
Sundowns fans out in the stands were evidently pleased to see their team scoring twice inside the opening 45 minutes, especially on a rainy weather which could have upset their free-flowing football.
Themba Zwane was a thorn in the SuperSport United defence throughout that period, but he went AWOL in the second half, although he had an attempt at goal some time towards the 65th minute.
The visitors kept going at Sundowns for the better part of the second half, and they were duly rewarded when a Modiba cross found Gould, who slotted the ball home with a clinical finish from close range.
Mosimane changed things around soon afterwards by introducing Toni Silva and Aubrey Ngoma in quick succession.
Silva had a chance to bury SuperSport United five minutes from time after beating the offside trap, but the Equatorial Guinea international fired wide with only Williams to beat.
SuperSport United had a strong finish to the game, but in the end, they still couldn't beat Onyango for the second time on the afternoon.
Mind you, Onyango came into this encounter having conceded only twice in seven league matches this season.