Previously winless MI London somehow recovered from the depths of both 23-5 and 64-8 to defend 122 and win by three runs.
New Zealand superstar Kerr single-handedly dragged her side to their defendable total with a brilliant unbeaten 69, and Spirit fell short, despite taking it to the last ball.
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Kerr said: "It was pleasing to get a win today and a great game for the crowd in the London derby, and really nice to be on the winning team! We showed a bit of maturity and mental toughness, the wicket was tricky and once we got past 100 everything was a bonus, so 120 was great."
Following Kerr's effort with the bat, the MI London bowling attack scrapped for every wicket, with Spirit's batters unable to break the shackles and when the South African pair of Marizanne Kapp and Nadine de Klerk went late on, the game was up despite a couple of late Deandra Dottin boundaries.
Spirit, who have lost six in a row at HQ, lost the chance to move up the table, MI London joining them on six points with this thriller coming after an equally exhilarating tie in the reverse fixture at the Kia Oval.
Spirit's attack made early inroads after they won the toss, restricting the visitors despite Kerr's brilliance, which was largely responsible for 55 runs coming in the last 25 balls.
Kapp and Katie George bowled 10 each up front, at which point the score was 14-2, but it was the introduction of Charlie Dean after 30 balls that derailed MI London. She also bowled 10 straight through, picking up 3-6.
Kerr and Chinelle Henry, who had saved MI London with a stand of 55 at the Kia Oval, counter-attacked before the West Indian pulled De Klerk straight to deep square.
Kerr stood firm, striking her first competition six in her 26th game in The Hundred, hitting a second to dent Dean's figures and then smiting her for two more for good measure, the fourth brilliantly deposited over cover.
MI London broke through early with the ball, sending back Grace Harris and Marie Kelly and when the experienced Amy Jones also went to leave the home side on 36-3, nerves started jangling.
Dean steadied things with the unflappable Kapp before she was castled, a lack of boundaries causing the pressure to mount. At the halfway stage it was 54-4 and Kapp was joined by De Klerk, the two playing with common sense to take the score to 93 before Kapp chipped match-winner Kerr to midwicket.
With the tension mounting, De Klerk picked out deep square having been dropped the ball before. Dottin, held back to No 9, hit successive fours but it was too little too late as MI London broke their duck.
What is happening in The Hundred on Friday?
Friday sees a single double-header as Birmingham Phoenix women's team host SunRisers Leeds from 3pm before the men's sides square off from 6.30pm. Catch both fixtures live on Sky Sports.
Watch every match of The Hundred through to the finals on Sunday August 16. Watch The Hundred and more contract-free on NOW
