Relishing the opportunity to increase their gap at the top of the table to 13 points with victory against Roma, the pacesetters began full of confidence and immediately played on the front foot.
Khvicha Kvaratskhelia particularly threatened in the opening minutes, but he was superbly denied by Rui Patrício, as Roma began to grow into the game.
They too came close to opening the scoring thanks to a mixup in the Azzurri’s backline, as Kim Min-Jae almost headed the ball into his own net after a miscommunication with Alex Meret.
Napoli regained some composure after that scare, and Kvaratskhelia’s cross into the box was superbly controlled by Victor Osimhen - first with his chest, then his knee - before he unleashed an unstoppable volley into the roof of the net.
The Giallorossi responded well after falling behind and came close to equalising right on half time, but Meret did well to deny Leonardo Spinazzola’s stinging effort from the edge of the box, diving dramatically to his right and parrying the effort away to safety.
Roma came flying out in the second half, putting the home side under immense pressure with Bryan Cristante coming closest with a header from point-blank range, but Meret superbly denied the Italian.
From the resulting corner, Napoli broke through on a counter-attack with blistering pace in a three-on-two situation, but Hirving Lozano chose to go through alone and his solo effort was tipped over the bar by Patrício.
Napoli would seemingly be made to pay for that failure to convert with 15 minutes remaining, as Stephan El Sharaawy popped up at the back post to prod home Nicola Zalewski’s searching cross.
There was to be a late twist though, as Simeone came off the bench to secure an 86th minute winner, with a superb turn and curling finish into the top corner to spark delirium at the Diego Maradona Stadium.
The late winner could prove Jose Mourinho to be correct, after the Roma boss congratulated Napoli for already winning the Scudetto during a pre-match press conference.
Whilst Napoli's first title in 33 years isn’t theirs just yet, today’s earlier results involving Lazio and AC Milan combine well with this success, suggesting that it may just be a matter of time for Gli Azzurri.
Flashscore Man of the Match: Victor Osimhen (Napoli)
