Jacques Brunel's side battled valiantly in the first half, with the boot of Kelly Haimona keeping them in touch with the Springboks, who only led 8-6 at the break.
However, the New Zealand-born fly-half missed a long penalty 16 minutes after the restart that would have put Italy 9-8 up - and that proved costly, as South Africa moved through the gears thereafter.
Tries from Cobus Reinach and Bryan Habana contributed to a comprehensive final score, as Heyneke Meyer's side extended their record to 12 wins from 12 meetings with Italy.
After an evenly matched start, Italy edged ahead in the 11th minute courtesy of Haimona's first penalty.
Pat Lambie levelled matters with a kick of his own, before normal service appeared to have been resumed when Coenie Oosthuizen - recalled to the Springboks' side after last week's win over England - barged over for the opening try following some excellent pressure.
Lambie missed the resulting conversion, and Haimona kept Italy in it with another penalty on the stroke of half-time.
The beginning of the second period mirrored that of the first, with very little fluency from either team.
Haimona missed a tough, 50-metre penalty after 56 minutes that would have put Italy back in front - and the Zebras man was soon made to pay, as Reinach scored his second try in a week having opened his Springboks account at Twickenham.
Debutant Nizaam Carr came off the bench and made an immediate impact, with his superb break ending with Reinach going over under the posts.
Handre Pollard, who was also called on from the bench early in the second half, added the conversion to give South Africa a measure of comfort at 15-6 up with just 16 minutes remaining.
Meyer's side saw out the closing stages with typical control and composure and Habana added some gloss to the scoreline in the last minute.
The wing - South Africa's all-time leading try scorer - crossed for his 57th international score after more good work from the impressive Pollard, who subsequently kicked the conversion to round off a comfortable win.
South Africa will now look to round off their November tour of the Northern Hemisphere with victory over Wales next week.