Batting at number six, Pandya struck a brilliant 59 not out off 28 balls that rescued the home team from a compromising position of 78-4 in the 12th over to post 175-6 in their 20 overs.
Lungi Ngidi and Lutho Sipamla had put India in early trouble with Ngidi eventually finishing with figures of 3-31 in four overs while Sipamla took 2-38.
The Proteas then could not cope with a disciplined India bowling attack as the visitors were dismissed for a paltry 74 all out, their lowest total in T20Is.
The highest individual score came from Dewald Brevis, who made 22, with only three other players reaching double-figures.
Pandya also contributed with the ball, grabbing the key wicket of experienced middle-order batter David Miller for a single.
The heavy defeat will be disappointing for the Proteas, as they look to get their combinations right ahead of the T20 World Cup early next year.
The second match of the five-match series takes place in Chandigarh on Thursday.
Temba Bavuma suffered his first defeat as Test captain after the Proteas went down by 214 runs against Australia in Durban, and the home skipper could not hide his disappointment.
Aiden Markram battled for almost six hours at the crease but a career-best bowling effort from Josh Hazlewood saw Australia complete a 214-run win against the Proteas in the first Test in Durban.
The Proteas will face a battle on the final day to save the opening Test against Australia in Durban, going to stumps on 102-4 after being set a target of 421.
Australia have earned a 139-run lead over South Africa after bowling out the lacklustre hosts for 284 runs in their first innings at Kingsmead Stadium on Sunday.
