Requiring just one more point to book their flights to Germany with two games to spare, the Three Lions were stunned by an early Gianluca Scamacca finish, but Harry Kane's brace, Marcus Rashford's strike and a dazzling all-around display from Jude Bellingham all played their part in sealing qualification for Gareth Southgate's troops.
No fewer than 11 changes were made by Southgate following their uninspiring friendly win over Australia, while Italy's crop were not safe from Luciano Spalletti's rotation following their crushing of Malta.
The much-changed hosts started the brighter under the Wembley arch and had a sighter of goal in the 12th minute, but Rashford's 25-yard free kick fizzed over the crossbar.
However, as was the case on Friday, chance creation was still proving a problem for the men in white, and they were hit with a Scamacca-sized sucker punch in the 15th minute, as the ex-West Ham United man marked his return to London in style.
The Azzurri switched from left to right during a quick counter-attack, and Giovanni Di Lorenzo's cross from the byline found Scamacca, who was inexplicably left unmarked in the centre of the goal and fired home into the roof of the net from close range.
While Harry Maguire went with Davide Frattesi at the front post, John Stones was nowhere to be found as Scamacca netted his first-ever senior Italy goal, which flattened an already-subdued Wembley atmosphere further.
However, the hosts' two star men combined to devastating effect on the stroke of the half-hour mark, as Kane held the ball up for Bellingham, who charged through the middle into the penalty area and was scythed down by Di Lorenzo.
Clement Turpin's decision to award a penalty was eventually upheld after a lengthy VAR check, and Gianluigi Donnarumma's previous penalty prowess at Wembley counted for nought against Kane, who calmly sent the Paris Saint-Germain stopper the wrong way for his 60th England goal.
Both Donnarumma and Jordan Pickford were called into action towards the end of the half to deny Rashford and full Italy debutant Destiny Udogie respectively, but it was another 20-year-old who would set the stadium alight 12 minutes into the second half.
After winning the ball back close to his penalty area, Bellingham sparked an England counter-attack with a sumptuous touch over an onrushing Giorgio Scalvini on the halfway line, and the Real Madrid hotshot proceeded to lay off Rashford, who cut inside and hammered a low strike into the bottom corner with aplomb.
England enjoyed a relatively trouble-free next 10 minutes, but Kalvin Phillips was highly fortunate not to receive a second yellow for catching Scalvini with his studs and was soon withdrawn for Jordan Henderson, whose introduction was predominantly met with cheers after he was booed off against Australia.
A few audible boos were still heard, but the entire Wembley faithful were in full voice in the 77th minute, as captain Kane rubber-stamped his nation's place in next year's Finals.
Marc Guehi's long ball over the top found the Bayern Munich man, who comfortably outmuscled and spun Alessandro Bastoni, prodded the ball past Scalvini and made no mistake one-on-one with Donnarumma.
Moving onto 16 points from their five matches in Group C, England are also guaranteed to qualify for the Euros in first place, as Ukraine's inferior head-to-head record means that the Blue and Yellow - who beat Malta tonight - cannot usurp Southgate's team.
The Three Lions round off their successful qualifying campaign against Malta and North Macedonia next month, while Spalletti's side - who have dropped to third - meet the latter before a possible winner-takes-all tie with Ukraine on the final matchday.