Michael Morton almost opened the scoring for AmaZulu in the second minute with a cracking shot from outside the box that sailed over the bar.
Siyabonga Nomvethe eventually opened the scoring for Usuthu in the 11th minute with a close range finish after he was setup by Ovidy Kururu from the right wing, 1-0.
Thuso Phala was unlucky not to find the equaliser in the 21st minute after his thumping shot from outside the box hit the upright.
Teboho Mokoena had a chance in the 36th minute to find a reply but his curling strike from the edge of the box was saved by Siyabonga Mbatha.
Karuru made it 2-0 to Cavin Johnson's charges on the stroke of halftime with a gift of a goal following a sloppy pass from Reyaad Pieterse that the Zimbabwean intercepted and duly slotted away.
Kingston Nkhatha almost pulled a goal back 10 minutes into the second half with gliding header inside the box but it sailed wide of the target.
Matsatsantsa were awarded a penalty two minutes after the hour after Nkhatha was brought down in the box but Mbatha produced a great save to deny Aubrey Modiba from 12-yards out.
In the 72nd minute, Morgan Gould had a chance to pull a goal back but his header from the centre of the box sailed over the crossbar.
Modiba had an opportunity after 85 minutes with from a free-kick in a dangerous area but his curling shot went over the bar.
Matsatsantsa threw numbers forward in the last minutes but they unable to bypass the Usuthu defence.