Giacomo Raspadori struck twice as Sassuolo beat AC Milan 2-1 at the San Siro on Wednesday, hours after the hosts were forced to backtrack on their plans to join a European Super League.
Italian forward Raspadori came off the bench in the second half and scored twice in a seven-minute spell, after Hakan Calhanoglu had put Milan ahead on the half-hour mark.
Second-placed Milan's slim title hopes now appear all but over as Stefano Pioli's men remain nine points behind leaders Inter Milan.
Their bid for a return to the Champions League for the first time since 2014 is also still at risk.
Third-placed Atalanta, who are two points behind Milan, travel to Roma on Thursday, while the other top-four hopefuls -- champions Juventus, Napoli and Lazio -- are also all in midweek action.
Inter can open a 12-point lead on their city rivals when they visit Spezia later on Wednesday.
The defeat came after Milan bowed to pressure from fans and accepted the failure of the ill-fated Super League.
Sassuolo coach Roberto De Zerbi had threatened to boycott the game because Milan were among the 12 founding clubs.
Before kick-off, Milan club director Paolo Maldini apologised to fans.
"I want to make it clear that I have never been involved in discussions, I learned it on Sunday night like you did," said Maldini.
"But that does not exempt me from apologising, not only to the Milan fans but to all the supporters in general."
Milan were without star striker Zlatan Ibrahimovic with a muscular problem, with Theo Hernandez and Ismael Bennacer also sidelined.
But Calhanoglu broke the deadlock with a superb strike from a tight angle after a perfect Alexis Saelemaekers cross.
Diogo Dalot did well to block a Domenico Berardi shot for the visitors before the break.
Sassuolo goalkeeper Andrea Consigli denied Saelemaekers 10 minutes into the second half and saved from Calhanoglu six minutes later to keep his side in the game.
Raspadori, 21, came off the bench and pulled his side level with 14 minutes to play and grabbed the winner in the 83rd minute.
Milan suffered their fifth home league defeat of the season.
Eighth-placed Sassuolo claimed a third consecutive win but are nine points off the European places.
"My heart is still pounding," said Raspadori. "It's a great satisfaction scoring in this stadium. We are never dead and believe in Europe."