Scrumhalf Grant Williams, centre Canan Moodie, hooker Malcolm Marx, wing Makazole Mapimpi and replacement hooker Jan-Hendrik Wessels also crossed for tries in a performance that was far from perfect but enough to see off the Italians, who were ferocious at the breakdown but ultimately out-gunned.
The home side lost number eight Jasper Wiese to a needless permanent red card on 21 minutes for a headbutt, but made light of that numerical disadvantage on a night where fullback Willie le Roux became the eighth Springbok to win 100 caps.
Coach Rassie Erasmus introduced some innovative plays, including intentionally conceding a scrum from the kick-off, and twice creating midfield "line-outs" with lifting in open play that led to driving mauls and ultimately tries.
South Africa dominated Italy in the scrum in last week’s 42-24 win in Pretoria and forced a set-piece immediately from their own kick-off to keep the pressure on in what is surely a first for test rugby.
Williams and Van der Merwe crossed for eye-catching scores, before the home side were reduced to 14 players when Wiese was given a red card for a head-butt on Italy prop Danilo Fischetti as they came together following a stoppage in play.
What was supposed to be a joyous occasion for Wiese with his younger brother Cobus debuting off the bench turned sour.
Italy’s intensity at the breakdown, a key area they have targeted in both tests, made it chaos on the floor and denied the Springboks quick ball.
But there was more Springbok innovation in the build-up to their fourth try for Moodie as, in broken play, lock Ruan Nortje was lifted in centre-field to collect a pass.
That created a maul and allowed them to drive forward, winning a penalty for an Italian collapse, but also setting Moodie free to score his try.
They repeated the play in the second half and again won a penalty they did not need as Marx barged over the line, before Mapimpi and Wessels dotted down late on.
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