The Proteas - minus their Indian Premier League stars - had slipped to defeat in the opening game on Saturday but recovered impressively from that setback, with a disciplined bowling performance restricting their opponents to 140-9.
Aidan Markram led the reply with 54 from 30 balls and while there was a mid-innings wobble as they slipped to 98-4, the hosts still cruised to their victory target with six overs to spare.
Stand-in captain Heinrich Klaasen finished up unbeaten on 36, while George Linde was 20 not out from just 10 deliveries to complete a fine all-round performance.
Mohammad Rizwan had starred in Pakistan's successful run chase at the weekend, making an unbeaten 74, but fell for a first-ball duck this time.
The recalled Sharjeel Khan – playing his first international game since January 2017 – also departed early for eight, leaving the score at 10-2 in the third over of an innings that simply never gained momentum.
Skipper Babar Azam made 50 at a run-a-ball rate and Mohammad Hafeez contributed 32, the pair adding 58 for the third wicket.
However, three wickets apiece for Linde – who opened the bowling with his left-arm spin - and Lizaad Williams restricted Pakistan's final score. Tabraiz Shamsi also played his part with the ball, recording figures of 1-22 from his four overs.
The two teams meet again in the third T20 at Centurion on Wednesday, with the series concluding at the same venue two days later.
FIFTY!April 12, 2021
Rare failure for Rizwan
Rizwan had posted scores of 74 not out, 42, 51, 104 not out and 89 in his previous five T20 appearances for Pakistan. However, the impressive run of form came to a rapid halt on Monday.
The wicketkeeper-batsman fell to the first ball of the game, an ambitious attempt to hit Linde over the top only providing catching practice for Markram at mid-off.
Opening case continues
Markram made sure South Africa had no issues with the required rate in reply, hitting seven fours and three sixes in a 30-ball knock.
The opening batsman has hit back-to-back half-centuries in the format now, furthering his case for a spot in the full-strength line-up ahead of the T20 World Cup later in the year.