Australia 226 for 3 (Lanning 133*, Mooney 54) beat England 133 for 9 (Winfield 33, Schutt 3-25) by 93 runs
The 93-run victory meant Australia won the Ashes outright with a 10-2 points lead, an 8-8 series draw the most England could have hoped for going into the match at Chelmsford, where they had been unbeaten in 14 limited-overs internationals.
Lanning took that option off the table early, guiding Australia to their highest T20I total.
"That was our big priority coming over here, was to win the Ashes outright and today was a really big game," Lanning told Sky Sports. "It was nice to get on the front foot early and put England under pressure.
"I said to Beth Mooney out there, 'this is too much fun, let's keep going.' It was one of those days where everything clicked. I got away with a few early and the wicket was really good. It was coming onto the bat nicely and any width you were able to hit through the line and the outfield was pretty quick as well."
Having missed seven months after undergoing shoulder surgery following Australia's 2017 World Cup semi-final exit, ruling her out of the last edition of the Women's Ashes, Lanning made up for lost time. Her unbeaten 133, reached off just 63 balls, was the highest individual innings in women's T20 Internationals.
Lanning scored 88 not out early in her comeback when Australia inflicted England's previous worst T20I defeat - by 57 runs in the tri-series in India in March last year. It was there that Australia also posted their previous highest T20I total of 209 for 4.
England were without first-choice keeper Sarah Taylor, who withdrew from the T20 leg of the series as part of the ongoing management of her anxiety issues. She was replaced behind the stumps by Amy Jones, with accomplished fielder Fran Wilson coming into the squad but not selected in the team.
The hosts had a poor evening in the field, highlighted by Lanning's let-off on 85 when Tammy Beaumont put down a straightforward chance at point. By that stage, Australia were 143 for 2, having just lost Mooney after a 134-run partnership with Lanning.
Mooney struck 54 off 33 deliveries before Sophie Ecclestone broke up the pair, tempting the batsman down the pitch as she looked to loft the ball over the leg side but skied to Lauren Winfield at mid-off instead.
Lanning overcame being struck on the helmet in the jaw area by a ball fired in from the field by Natalie Sciver as she completed a run early in the innings. Unruffled, she nonchalantly hit Ecclestone for consecutive fours on the last two balls of the over. It was an early indication of the clarity and determination Lanning would show through the rest of her innings in which she picked off boundaries - 17 fours and seven sixes - to all areas of the ground with a combination of power hitting and clever placement.
She went to her second T20I hundred with a six swung into the crowd at deep square leg, and continued to cash in during the closing overs, hammering home the ruthlessness of Australia's victory.
Australia coach Matthew Mott described it as one of the best T20 innings he had seen.
"I think it was a masterclass of playing good cricket shots," he said. "She just went out there from ball one with great intent, hit the ball along the ground a lot and just threaded it through the field and it was great to watch.
"Also Beth Mooney, I thought, really set the tone early and having that left and right-hand combination was really important for us. It was pretty much the perfect batting innings and then we did what we had to do with the ball and we held on really well."
Lanning's cool-headed knock was just what Australia needed, too, after losing the wicket of Alyssa Healy on the fifth ball of the match when the opener skied a Kate Cross delivery to Sciver, who took an excellent overhead catch running back from midwicket. It also meant Ellyse Perry, the star of Australia's 3-0 ODI series sweep and last week's drawn Test, entered with just three overs remaining. She was not out on 7 at the close after Ashleigh Gardner had contributed a handy 27 off 14 balls.
Megan Schutt was the pick of the Australia bowlers, who collectively picked up where the batsmen left off, keeping England under pressure. Schutt dismissed opener Jones for a duck on the way to claiming 3 for 25 off her four overs.
Winfield and Katherine Brunt offered spirited cameos with 33 and 29 not out respectively, but the life had been sucked out of the England team long before.