The AmaZulu goals were scored by Goodman Dlamini and Thamsanqa Sangweni while Eleazar Rodgers pulled a goal back late in the game for Santos.
The defeat came as a setback to the Cape side's new caretaker coach, Duncan Crowie, who has taken over from Boebie Solomons for the final two games of 2011.
Both teams took their time to settle into any kind of rhythm with the result that neither goal came under any pressure in the opening 17 minutes.
Indeed the game lacked in spark or cohesion, with early chances limited to long range shots, all of them well wide.
The first real chance fell to the visiting team as Kagiso Senemela squared the ball for Goodman Dlamini, but his shot was weak and Ryan Harrison made a comfortable save.
Santos then began to find more thrust in attack as Phikolomzi Kefile fired a powerful drive just over before Vuyisile Wana flashed an effort wide from out on the left with 30 minutes gone.
With two minutes left in first half regulation time, Usuthu took the lead, thanks to Goodman Dlamini's strike from 12-yards out, which was going on target, but also took a slight deflection which left Harrison unable to make up the ground.
Santos started the second half in an attacking vein, but only had an Erwin Isaacs shot, which dipped onto the roof of the net, to show for their early efforts.
And when some neat interplay around the Santos box allowed Tamsanqa Sangweni to surge goalwards, he made it 2-0 after 55 minutes with a neat left-footed finish into the bottom corner.
Marc van Heerden came close to making it 3-0 in the 69th minute with an audacious chip from just inside the Santos half, but Harrison got back quick enough to claim the ball on his goal line.
There was a chance in the 85th minute for Eleazar Rodgers to pull a goal back for the Peoples' Team, but his header lacked accuracy.
Three minutes into injury time and Rodgers did get on the scoresheet when he headed in Kefile's cross from two yards out, but there was not enough time left for the hosts to muster a comeback.