Downs had a sluggish start to the season after being booted out of the MTN8 and being held to a goalless draw against Platinum Stars in their league opener.
A brace from Cuthbert Malajila and goals by Khama Billiat and Teko Modise handed Sundowns maximum points.
Daine Klate scored twice for the Students.
“It was a difficult game against a good team,” conceded Mosimane, “they are title contenders and have a good coach. It is still too early, but it is an ice-breaker.
“I told the boys that if they want to win the championship, they must start winning games like this against credible opponents like Wits.
“Games like these are title-winning games,” added Mosimane.
“I am not saying we will win the title – I would like to win it obviously – but these are title-winning games.”
Wits coach Gavin Hunt felt they were hard done by and didn’t deserve the defeat after dominating the better part of the match.
The outspoken coach hinted that the officiating on the day left much to be desired.
“Malajila scored two goals, but he should have been off the field in the first half with a red card. Penalties? What can I say?
“The scoreline is not a true reflection, but that’s football.”
The Brazilians meet Mpumalanga Black Aces on Tuesday evening, while the Clever Boys host Maritzburg United on Wednesday.