Harry Kane's first half penalty sealed his England legacy, becoming the country's all-time record goal scorer with 54.
The striker surpassed Wayne Rooney's previous record of 53, a record that had stood since September 2015.
The landmark achievement comes just 46 days after Kane broke Jimmy Greaves' record to become Tottenham Hotspur's leading talisman.
His penalty doubled England's lead on the brink of half-time after Declan Rice opened the scoring 13 minutes into the game.
Italian debutant Mateo Retegui pulled a goal back for Italy shortly after the break, but the visitors held on for a crucial three points.
Gareth Southgate's side went down to 10 men in the dying stages as Luke Shaw picked up two quick yellow cards, but England held on to win their opening game of Euro 2024 qualification.
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Story of the Match
After missing the 2022 World Cup, Italy were getting ready to play in their first competitive game since facing Hungary in the Nations League in September.
Roberto Mancini made six changes to his last eleven, a side that lost 2-0 to Austria in November.
Rafael Toloi and Leonardo Spinazzola were introduced to the defence as gli Azzurri reverted to a back four.
Arsenal man Jorginho was also recalled, joining Nicolo Barella and Marco Verratti to create a three man midfield.
Domenico Berardi and Lorenzo Pellegrini were both recalled into the front three while striker Retegui made his international debut. The 23-year-old has scored six goals in eight games in the Argentinian Liga Profesional with Tigre this campaign.
Southgate opted for a much more conservative approach with his 11, making only two changes from England's World Cup quarter-final defeat to France.
Liverpool's Jordan Henderson made way for the surprise return of Kalvin Phillips. The Manchester City man has played 13 games since his summer transfer from Leeds United.
Jack Grealish replaced City teammate Phil Foden in the front three, partnering with Kane and Bukayo Saka in attack.
Italy had the first chance of the game as Giovanni Di Lorenzo shanked a volleyed effort wide of goal after getting on the end of a Pellegrini free kick.
It was an effort that the hosts would rue as England began to take hold of the game from that moment.
Saka had England's first shot of the game, racing into the area and forcing Gianluigi Donnarumma to make a comfortable save.
Jude Bellingham would try his luck shortly after, driving at the heart of an out of shape Italian backline before unleashing a vicious effort on goal. The 19-year-old forced Donnarumma to tip the ball over the crossbar.
The deadlock would be broken from the resulting corner. Saka's in-swinging delivery found the feet of Kane, whose effort was deflected into the path of Rice. The West Ham man fired home a left footed effort from eight yards out, giving England something to show for their early dominance.
The match seemed to settle into a calmer rhythm as England controlled possession with some slick one-touch football.
The returning Phillips came close to doubling England's lead in the 32nd minute, striking narrowly wide from the edge of the box. The chance came after Bellingham dispossessed Acerbi in the attacking third.
Another Saka corner caused Italy problems, this time as the ball hit the arm of full-back Di Lorenzo. Incensed England players surrounded referee Srdjan Jovanovic before the Serbian official checked the VAR monitor and awarded the visitors a penalty.
All eyes were on Kane. England's number nine stepped up to take the penalty 103 days after his World Cup miss, this time firing home into the bottom right corner.
A visibly relieved Kane wheeled away to the corner of the pitch as he celebrated his record-breaking moment, surpassing Rooney as England's all-time top goal scorer.
Southgate's side should have had a third soon after kick off. Kane's ball across the box found an unmarked Grealish at the back post, but the City man scuffed his effort wide of an open goal.
A dominant first half performance saw England head into the half-time break 2-0 up.
The hosts looked have more impetus to their play at the start of the second period, although a string of corners soon after the break failed to seriously test England.
Five minutes after half-time, Italy captain Veratti found Pellegrini in the channel before the Roma man fired his effort over the bar under pressure from Kyle Walker.
They would not have to wait long until they got another opportunity, this time pulling a goal back. Pellegrini this time turned provider, playing a no-look pass into the feet of debutant Retegui, allowing the striker to finish calmly across Jordan Pickford's goal.
Harry Maguire picked up a yellow card in the build up to the goal for a late challenge on Barella.
The hosts looked to pile on the pressure but struggled to create clear cut chances in search of an equaliser. Coach Mancini introdcued Wilfried Gnoto and Matteo Politano as he looked to inject some life into his attack.
Momentum shifted further in the hosts favour in the 80th minute as Shaw was dismissed for a second yellow card. The left-back picked up two bookings in quick succession for time wasting and a tactical foul.
Kieran Trippier entered the fray, replacing Foden who had come on as a substitute just 12 minutes prior.
A late Italian onslaught followed, but again the hosts failed to test goalkeeper Pickford in the later stages of the game.
West Ham striker Gianluca Scamacca was introduced with two minutes of normal time to play, but his presence was counteracted by England's switch to a five man defence.
As Italy got frantic, England looked stable and as Rice sent the ball flying down field, the referee called time on the game.
The result means England have beaten Italy away from home for the first time in 62 years, and for the first time in six attempts, dating back to August 2012.
England sit top of qualifying Group C along with North Macedonia. They will travel back to Wembley to face Ukraine on Sunday.
As for Italy, it already feels like a damaging defeat in the race for qualification. They travel to Malta on Sunday evening knowing that a win is essential.
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Player of the Match
Declan Rice was at the heart of England's spectacular first half, as well as looking comfortable under pressure in the second.
The 24-year-old notched his third England goal on his 40th appearance this evening, becoming the fourth West Ham man to reach the 40 cap mark for England.
Rice did pick up a booking in the first half for time wasting, although it did feel soft given his lack of fouls up to that point.