France was leading 20-16, but second-row forward Itoje's score, awarded by the television match official (TMO) and then converted by skipper Owen Farrell, extended its 16-year-wait for a win over England at Twickenham.
Victory saw reigning champion England bounce back from its controversial 40-24 defeat by Wales last time out, a loss that was greatly influenced by French referee Pascal Gauzere's mistakes, by his own admission.
It took France just two minutes to score the opening try of the match through star scrum half Antoine Dupont.
England, however, hit back through Anthony Watson's try before two penalties from captain Owen Farrell saw it into a 13-7 lead.
France responded with a Matthieu Jalibert penalty before the five-eighth converted Damian Penaud's try to give Les Bleus a 17-13 lead at half-time.
Jalibert and Farrell exchanged penalties early in the second half before Itoje powered his way over late on.
Referee Andrew Brace initially decided that Itoje had been held up by Teddy Thomas and Cameron Woki but consulted TMO Joy Neville to make sure, and she ruled that the lock had grounded the ball.
It was a sweet moment for Itoje after he had given away several penalties against Wales.
France, which had already defeated Italy and Ireland, kicked off having had an extended break after its third-round match against Scotland was postponed because of a coronavirus outbreak in its squad.
A second-string France had pushed England all the way before losing the Autumn Nations Cup final at Twickenham in December in sudden death extra-time.
But that still left Les Bleus searching for their first win over England since 2005 when Dimitri Yachvili kicked all of their points in an 18-17 victory.
England had already seen its hopes of a successful title defence ended by losses to Scotland and Wales either side of a win over perennial struggler Italy.
Eddie Jones, the England coach, benched senior players Elliot Daly and Jamie George, with full back Max Malins, given a full debut, and hooker Luke Cowan-Dickie taking their places.
But it was not long before Malins was left stranded.
France regained possession after an England box-kick and an eight-phase move saw powerful centre Virimi Vakatawa break clear.
He in turn found wing Teddy Thomas, who chipped over the head of Malins and Dupont, underlining his reputation as a brilliant support player, beat the England cover to touch down.
Jalibert added a tricky conversion and France led 7-0.
England then laid siege to the France line with a series of drives that led to a five-metre scrum. But when the ball was worked behind the pack, the chance of a try disappeared with Malins's wild pass into touch.
But England was level in the 10th minute when a break by centre Henry Slade created an overlap out wide that allowed wing Watson to mark his 50th England cap with a 22nd Red Rose try.
Farrell converted and his two subsequent penalties, either side of a dynamic break by Watson that was a sign of the team's increased willingness to attack from deep, saw England pull clear at 13-7.
Jalibert grounded a chip ahead on his own leg but, with Brace having played an advantage, he kicked a simple penalty in the 29th minute.
Three minutes later, France was back in front.
From a lineout, centre Gael Fickou sold a fine dummy before Jalibert's excellent lobbed miss-pass found wing Penaud in space for a try.
Jalibert and Farrell both landed penalties to leave France 20-16 ahead going into the final quarter before Itoje just did enough to pierce the French defence.