Ireland's Jai Moondra and Matt Hollard dismantled the Indian batting line-up with three-wicket hauls as the visitors could only manage 9-153 after Ireland, put in to bat, posted 8-154 on a rain-disrupted afternoon in Belfast.
The hosts, who earned their first-ever victory over India on Friday, handed the visitors their first T20 series defeat since 2023.
"I challenged the lads the other day to show the world that (the first win) wasn't a one-off," said Ireland captain Lorcan Tucker.
"We have a lot of lads with very few caps but they showed great character... it is a great time to be a professional cricketer in Ireland."
Ireland made a shaky start as their openers fell in the first three overs and Prince Yadav (3-22) making his T20 debut for India, helped restrict the flow of runs in the first half of the innings.
But Harry Tector (53) and Ben Calitz (37) helped Ireland recover and post a competitive total.
In reply, player-of-the-series Moondra (3-32) dismissed Indian openers Sanju Samson and Abhishek Sharma in the very first over, and bowled captain Shreyas Iyer in the third over, leaving India reeling at 3-19.
Tilak Varma's fighting knock of 55 kept India in the hunt, but Hollard (3-26) got him caught by wicketkeeper Tucker, dealing a crucial blow to the visitors' hopes.
Harshit Rana (21 off 10 balls) got the visitors close, and they needed eight runs to win from the last two balls. But Rana was caught trying to hit Tector for a six off the penultimate delivery to seal Ireland's win.
"Kudos to (Ireland), the way they played. Showed professionalism, they had tremendous idea of how the wicket was going to play," Iyer said.
India next visit England for a five-match T20 series starting July 1, followed by three 50-over matches.
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