Le Roux's electric display set alight a contest that was otherwise strewn with set-piece and handling errors.
He scored one excellent individual try and created two others for wing Bryan Habana. Cornall Hendricks and Duane Vermeulen also crossed the line for the hosts.
Wales offered little in the opposing 22 until the final 15 minutes and were made to pay for a timid first half display.
Their only try came following a break in his own half by wing Alex Cuthbert. Dan Biggar landed two drop goals and a penalty for the visitors.
The home side scored 21 points in as many minutes as they dominated the opening quarter using the width of the pitch to expose frail defending from the Welsh.
Their first touchdown was finished by Habana but came after a penetrating break from Le Roux and a kick from the fullback that was chased down by the wing just before the dead-ball line.
Wales were not helped by a yellow card received by centre Jamie Roberts after 12 minutes.
South Africa's second try had a little less finesse as number eight Vermeulen barged his way over from a few metres out.
Habana extended his national record for test tries to 55 when he got his second of the game and again it was Le Roux who was the creator, his break through the Welsh line and perfectly timed pass allowing the wing to dive over in the corner.
South Africa were dominating all facets of play by now and might have had more points but for some sloppy handling.
Their dominance in the pack saw Welsh prop Adam Jones, playing in his 100th international, replaced just past the half-hour mark by Samson Lee.
Le Roux capped his evening with a brilliant individual effort for the fourth try before halftime, collecting his own chip behind the defence and diving over in front of the goal posts.
And still he had more to give. His straight running and well-timed pass allowed Hendricks a debut try and provided a fifth conversion for Morne Steyn who put in a faultless kicking display.
Wales had precious few scoring opportunities and when they did cross the line with 20 minutes to go, debutant Gareth Davies's score was disallowed under review for a forward pass by Biggar in the build-up.
Cuthbert added some cheer for Wales with a fine breakaway try from his own 22, outsprinting the retreating defence with ease and offering a mesmerising sidestep that flummoxed Le Roux.
The second and final test will be in Nelspruit next Saturday.
