It was England's biggest win at a European Championship, and their biggest win in the knockout stages of a major tournament.
Gareth Southgate made two changes from the win against Germany - one of which was forced with Bukayo Saka out having picked up an injury in training, with Jadon Sancho coming in to make his first appearance of the tournament.
Having played every game up to this point at Wembley, a different atmosphere greeted England at the Stadio Olympico, but that didn't stop them from making the dream start.
Raheem Sterling found space to cut in from the left hand side and thread a neat ball through to Kane, who lifted the ball beyond the advancing Georgi Bushchan with just four minutes on the clock.
There had been question marks over the Tottenham striker after failing to score in the group stage, but after his goal against the Germans he looked back to his confident best.
England pressed high up the pitch when they didn't have the ball, restricting Andriy Shevchenko's side to limited possession. However, Roman Yaremchuk did seize upon a wayward pass from Kyle Walker but Jordan Pickford stood strong at his near post.
Despite their territorial advantage, England struggled to turn their dominance into goals with Declan Rice seeing a rasping effort beaten away by Bushchan before Luke Shaw fed Sancho who had his shot saved by the Ukrainian stopper.
At 1-0 going into the break, England would have wanted a good start to the second half - and they did just that as the Three Lions flexed their muscles from set-pieces.
Maguire doubles the lead
Kane won a free-kick out on the left hand side and the impressive Shaw whipped in a great ball which Maguire met and he planted his header past Bushchan.
And things got even better for Southgate's men after 50 minutes. Sterling fed Shaw down the left and he lifted the ball across to an unmarked Kane, and his downward header found the net.
Kane almost got a hat-trick, but was denied a hat-trick with a fine save from Bushchan after a thunderous volley. But from the resulting corner, England breached the Ukraine defence once more.
Henderson gets his goal
Mount this time was the provider, whipping the ball in for Henderson to head home his first England goal on his 62nd cap for his country. Of all players to score at least once, Henderson's 62 games are the longest an England player has ever had to wait.
To add to England and Southgate's satisfaction, they kept their fifth successive clean sheet and are still yet to concede at Euro 2020 - having not conceded for 662 minutes.
Attention now turns to Wednesday night, and a semi-final tie against Denmark at Wembley. Football might be coming home after all...