The South African outfit raced into a 30-7 halftime lead thanks to two tries by Sarel Pretorius and one from Robert Ebersohn as they took advantage of needless errors by the home side to record a first ever win over the Highlanders.
Johan Goosen's perfect place-kicking added the remaining 21 points in a welcome first win of the season for the Cheetahs, who dominated possession and territory against the Waikato Chiefs last week but were hammered 45-3 by the defending champions.
Winger Kade Poki touched down three times for the Highlanders but the New Zealanders were unable to replicate their fightback in last season's corresponding fixture, when they overturned a 21-point deficit to win 36-33 in Bloemfontein.
Aside from Poki's contribution, the highlight for the beaten Highlanders was the comeback of Colin Slade after a year out with a broken leg. The All Blacks flyhalf got his opportunity when Lima Sopoaga's error-strewn performance was ended by his replacement shortly before halftime.
The Highlanders will now eye next week's encounter with the Wellington Hurricanes for a first win of the season.
The move for the Cheetahs' first try started from near halfway on the right touchline, from where the visitors moved the ball through several pairs of hands to Pieter Labuschagne charging down the left.
The open-side flanker handed off his tackler and slipped the ball inside to scrumhalf Pretorius, who ran in unopposed.
Goosen added the conversion and a penalty for Brad Thorn's off-the-ball obstruction to his earlier three-pointer to put the Cheetahs 13-0 up.
That stung the home side into action and they swiftly moved the ball through several phases for Sopoaga to send a little grubber kick through the defensive line for Poki to drop onto and score. Sopoaga had struck the post with his first effort on goal but made no mistake with the conversion.
The Highlanders were flying but a pair of intercepts put the game beyond them. Centre Ebersohn charged down a chipped kick from Sopoaga and ran in for an easy score before Willie Le Roux got fingertips to a risky pass by the same player, tipping the ball into the hands of Pretorius for the scrumhalf to race away and touch down.
Goosen smacked over another penalty in between his two successful conversions and suddenly it was 30-7.
The Highlanders fought back as soon as the second half kicked off, probing one way and then another to work a three-man overlap and put Poki in for his second try.
Slade missed the conversion and the best efforts of the home side resulted only in Poki breaking three tackles for his third try with eight minutes remaining.