The Tottenham Hotspur striker surpassed Wayne Rooney with a 54th strike to put Gareth Southgate's side 2-0 up after Declan Rice had drawn first blood, but the Azzurri threatened a late comeback after Mateo Retegui pulled one back.
Luke Shaw was sent for an early bath with 10 minutes to go, but Italy's valiant second-half efforts were ultimately in vain as England claimed a first win on Italian soil since 1961.
While England struggled to settle during a chaotic start, Italy's relentless pressing did not translate into any meaningful chances, and Gianluigi Donnarumma was the busier of the two goalkeepers early doors.
Bukayo Saka had the first sight of goal with eight minutes gone, but the Arsenal starlet could not get a decent connection on the ball under pressure, before Jude Bellingham's powerful drive four minutes later was tipped over by Donnarumma.
From the resulting corner, though, Saka's deep delivery to the back stick fell for Kane, whose shot was blocked before Rice found himself in the right place at the right time to crash home the rebound.
With their tails up, England thoroughly dominated the midfield battle as Bellingham and Rice ran a beleaguered Italy into the ground, potentially adding a few more pounds to their value in the process ahead of expected battles for their signatures in the summer.
Wanting his own slice of the action, Kalvin Phillips fired just wide of the post in the 32nd minute as Italy struggled to get a grip on proceedings, and another Saka corner to the back post was the catalyst for England's insurance goal in the 44th minute.
Before Kane could make the most of Saka's set-piece, the ball struck the outstretched arm of Giovanni Di Lorenzo, but referee Srdjan Jovanovic initially waved away the Three Lions' vociferous protests.
However, a spot kick was awarded following a quick look at the pitchside monitor, allowing Kane to send Donnarumma the wrong way for his record-breaking 54th goal in England colours.
The Tottenham Hotspur man let emotion take over as he basked in adulation, but disbelief was the main emotion for England in the 45th minute, as Jack Grealish missed a sitter at the back post just before the half-time whistle blew.
Galvanised by that late reprieve, Italy came out a different beast at the start of the second half and reduced the deficit in the 56th minute through Retegui's own landmark goal.
Referee Jovanovic played a smart advantage after Nicolo Barella felt the full force of a stamp to the foot from Maguire, as Lorenzo Pellegrini fed Retegui to fire into the far corner for a debut Azzurri goal.
Very rarely sauntering out of their own half in the second 45, England were firmly under the cosh as the game approached its dying embers, and Jovanovic took no prisoners when it came to time-wasting, booking Kyle Walker and Shaw for delay tactics in quick succession.
Only a couple of minutes after being booked for taking too much time on a throw-in, Shaw was given his marching orders for a second yellow card offence, bringing Retegui down to see red after 80 minutes.
England's 10 men were also seeing red - infuriated that Italy did not put the ball out with Maguire down just before Shaw's inexcusable tackle - and Bellingham limping off the field in the 85th minute was hardly a sight for sore eyes either.
However, Southgate's side survived five minutes of added time to see out a hard-fought success ahead of Sunday's meeting with Ukraine at Wembley, while Roberto Mancini's crop travel to Malta this weekend.