Sharks boss Jake White paid credit to his squad for responding to the losses of Paul Jordaan and Pieter-Steph du Toit with a win.
Promising young duo Jordaan and du Toit have both been ruled out through injury, with Jordaan back in a month but du Toit out for the season with an ACL injury.
S'bura Sithole and Stephan Lewies came in at centre and lock respectively in a test of the Sharks depth and the home side came through, with Pat Lambie kicking six penalties in a 35-20 victory over the Reds.
"This was not a normal week, said White.
"With the emotional backlog in that group, to come back and beat the Reds, who have a squad full of Wallabies, and have won this competition, I am very happy.
"I feel for them. Pieter-Steph du Toit is now one of the best players in the world.
"But every team has to face up to these challenges, and John Smit has always told me that this group of players can adapt to change."
White admitted that the Sharks went off the boil a little in the second half, as the Reds hit back with tries from Mike Harris and Will Genia to put pressure on the hosts.
"We started getting ahead of ourselves, when we had played solid rugby in the first half. When you give them loose balls like that, you make life difficult."
The Sharks remain top of the South African Conference with four wins from four.