McIlroy and Fleetwood will face Americans Xander Schauffele and Patrick Cantlay in the fourth and final foursomes match on Friday morning in Rome.
Italian Molinari, who is a non-playing vice-captain this week, and Fleetwood won all four of their matches together in Europe's Ryder Cup win five years ago in France, with the duo dubbed by fans and the media as 'Moliwood'.
"How Tommy played in France and in his last home Ryder Cup and the partnership he had - I just hope I can live up to Francesco, is really all I'm trying to do here," said the four-time major champion.
"So if I can live up to Francesco, I think we'll be okay."
Cantlay and Schauffele won their two matches as a pair in the USA's 19-9 thrashing of Europe at Whistling Straits in 2021, both in foursomes.
They have also won all three of the foursomes contests they have contested in the Presidents Cup and McIlroy admitted it is "an incredible record".
But European captain Luke Donald is just focusing on his own team.
"I haven't really given their pairings much thought, to be honest. Nothing really surprises me," he said.
"They're 12 very strong players. We know our work is cut out. They're going to be very strong, as they always are...
"The US are definitely confident, and we're going to have to play some good golf."
