The hosts were high in confidence coming off the back of their 2-1 series victory against New Zealand earlier this week, but half-centuries from India's Jemimah Rodrigues (69) and Yastika Bhatia (54) lifted India to a comprehensive victory.
While Amy Jones starred with the bat, making 67 off 48 deliveries to thrust herself into contention to open during next month's Women's T20 World Cup, England's batters struggled to score, with the hosts losing the wickets of Jones, Dani Gibson, Freya Kemp and Issy Wong for just nine runs as they fell short chasing a target of 189.
While Lauren Bell took three wickets, England also had difficulties removing Rodrigues and Bhatia, with India rattling their way to 50 runs in their fourth over off 23 deliveries. Issy Wong also struggled with the ball, conceding 27 runs off her first over, which included multiple wides and boundaries from Bhatia.
Bell's usual new-ball partner, Linsey Smith was rested for the match, with former England captain and Sky Sports commentator Hussain expressing his confusion at why.
"I'm not sure England are good enough at the moment, looking at recent performances in World Cups, to suddenly say: 'We'll give everyone a go and change our winning formula'," Hussain said.
"What has been the most successful formula for England in the powerplay is Lauren Bell at one end and Linsey Smith at the other end.
"What do they do? They rest Linsey Smith! She had a rest for six months in the winter.
"England didn't play an international game from October 29 until May, and they're now resting people. We're two weeks away from a World Cup, play your best side!
"Bring someone in, and they (Wong) go for 27; that momentum you've got from Lauren Bell (taking two wickets in the first over), that's washed away! That was England's undoing.
"India will jump on that because they're a very good side."
Jones stars as more questions emerge over England's top order
One of the biggest puzzles leading into this series against India was who Edwards would pick to open the batting for England during the World Cup.
Edwards admitted earlier in the week her batters "had been giving me headaches", with all of Danni Wyatt-Hodge, Sophia Dunkley, Alice Capsey, Heather Knight and potentially Nat Sciver-Brunt, if fit to play, fighting for three spots at the top of the order.
Sky Sports commentator and former England seamer Tash Farrant believes Jones has now thrust her name into the frame to open the batting following a stunning knock that saw her make her sixth T20I half-century off 32 deliveries.
"More confusion, and also I think diminishing the confidence of that series win against New Zealand," Farrant said when talking about selection.
"They knew India were going to be a step up from New Zealand.
"Now we've almost put another person at the top of the order with Amy Jones. I thought she batted really well tonight."
Wyatt-Hodge is expected to make a return from parental leave for this series, while it is unclear when Sciver-Brunt could return from a calf injury that also saw her miss the ODI and T20 series against New Zealand earlier this month.
Dunkley again struggled to build a big score, with the right-hander having now made scores of eight, 26, 22, and 16 in her last four T20 internationals.
"I'm confused about who is going to bat at the top of the order," Farrant said. "I presume Danni Wyatt-Hodge is going to come back at the top for England.
"Sophia Dunkley looks like she's struggling for form as well.
"I'm confused about what the batting order is. Almost seeing the players after this game, you feel like the confidence is going in the wrong direction as well."
Alice Capsey, who struck an unbeaten 74 during England's first T20 match against New Zealand, was dismissed for six runs, while Freya Kemp was caught by Richa Ghosh off a Deepti Sharma delivery for eight runs. Dani Gibson, meanwhile, was dismissed first ball by debutant Nandni Sharma.
"It feels to me England are kind of auditioning this top-order at the moment," Sky Sports' Mark Butcher said. "Surely they should be thinking about getting themselves prepared for the World Cup?"
"Before they selected the side, Davina Perrin could have played in the top of the order," Hussain replied.
"They've gone with the tried and trusted, and still they don't quite know who is going to be opening in the first game."
Hussain backs Knight despite poor performance
Knight, meanwhile, scored 21 runs off 24 deliveries before she was caught on the boundary by Rodrigues, off Sree Charani.
In her last four T20I matches, Knight has made 21, 18, 25 and 19. But despite struggling to build a big score, Hussain still backs the former England captain to perform.
"You don't change your mind based on one innings. I back Heather Knight because she's been a world-class player for a long time, and under pressure, you need people like Heather Knight. She's done it for a number of years.
"But she will know her last four innings, and in particular today, when you're making such a run chase, to get a run-a-ball 20, on the back of three run-a-ball 20s when the run rate is going through the roof, that's the easier role.
"The hardest role is coming in, and suddenly the rate is at 12s, and you haven't faced a delivery, and the field's out, and you're not in a power play and people have chewed up, the worst thing you can do - you're better getting out for a first-ball duck than you are getting 20 off 20 [deliveries].
"That injury, she didn't play T20 internationals for a year. That hamstring she pulled here was a serious one. She was out of the side in this format for a very long time. Maybe she's taking time to get going. She's not as mobile.
"She's not someone like Jemimah Rodrigues, who is putting away the bad balls, and she mentioned the running between the wickets. Knock it between the gap and come back for two. Jemimah looks a lot busier. They are both touch players. Heather Knight opens up the off side just as well as Jemimah does, but Jemimah is busier at knocking it into gaps if you're not hitting boundaries.
"But she [Knight] has been around long enough to know that that was not the innings that was needed if you're in a 180-run chase."
England vs India T20I series results/fixtures
All times UK and Ireland, all live on Sky Sports
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