After winning the opening match in Potchefstroom earlier in the week, the Proteas followed up with another composed display in a rain-affected encounter reduced to 14 overs per side.
Pakistan were restricted to 100/9, struggling to establish meaningful partnerships as wickets fell at regular intervals.
Ayabonga Khaka delivered a standout performance with the ball, claiming 3/10 in her two overs, while Masabata Klaas chipped in with 2/14.
Nonkululeko Mlaba, Kayla Reyneke and Marizanne Kapp each took a wicket to maintain pressure throughout the innings.
Aliya Riaz top-scored for Pakistan with 20 off 18 balls, and Ayesha Zafar added 13. Pakistan were also aided by 15 extras, including 12 wides conceded by South Africa.
In reply, the hosts reached 104/4 with four balls to spare. Captain Laura Wolvaardt anchored the chase superbly, finishing unbeaten on 40 from 29 deliveries.
Tazmin Brits contributed 29 off 25 balls before being dismissed in the ninth over, while Dane van Niekerk managed three before falling in the following over. Kapp added a steady nine from eight balls, helping Wolvaardt guide the side home.
South Africa's measured chase ensured the target was surpassed comfortably, securing the series ahead of the third and final T20 in Kimberley on Monday.
Kayla Reyneke enjoyed a dream debut with bat and ball, including hitting the winning runs off the final delivery of the game, as the Proteas Women beat Pakistan by five wickets in the first T20I in Potchefstroom.
The Proteas Women will host India in a five-match T20I series in April, Cricket South Africa (CSA) has confirmed.
Proteas Women's captain Laura Wolvaardt has surged to the top of the world batting rankings in ODIs after another standout series at home against Ireland.
South Africa wrapped up a comprehensive 3-0 series sweep over Ireland in Friday's final one-day international at the Wanderers, securing a six-wicket win after comfortably chasing down 206.
