Van Persie was suspended for the Netherlands' 2-0 defeat of Chile in their final group match but will be back to partner Arjen Robben in the tournament's deadliest attacking duo.
The pair scored three each during the group stage as the Dutch romped into the last 16 with three victories and 10 goals, more than any other team at the World Cup.
That rich vein of form makes them favorites against the Mexicans but their previous clashes have been remarkably even.
In six meetings, the Dutch have won three and the Mexicans two. Of the 22 goals in those matches - an average of nearly four a game - both sides scored 11, and their only previous meeting at the World Cup, in 1998, ended in a 2-2 draw.
Van Persie's return means Dirk Kuyt is likely to be relegated to the bench after starting against Chile, but if he does play, either from the outset or as a substitute, the 33-year-old will win his 100th international cap.
At the other end of the age spectrum, 20-year-old forward Memphis Depay is also likely to start on the bench despite scoring twice in his two appearances.
"I must be realistic," he told reporters at the Dutch training camp.
"With incredible players like Robben and Van Persie, it's logical that I sit on the bench. If you see what Robben can do with dribbling the ball it's unbelievable."
The Mexicans are largely injury free and were impressive in the group stage, beating Croatia and Cameroon and holding Brazil to a goalless draw in Fortaleza's Castelao arena, the setting for Sunday's showdown against the Netherlands.
Their defender Moreno played under Van Gaal at Dutch side AZ Alkmaar and knows a thing or two about the talent in the Netherlands squad.
"They were young guys like me and they were just starting their careers when I was there," said Moreno, who now plays his club football at Espanyol in Spain.
"They've grown up under the guidance of Van Gaal. With the players they have up front it's going to be a very difficult match."
Moreno said he hoped to hug the Dutch coach twice on Sunday - once before kickoff as a gesture of friendship and again after the final whistle to commiserate him in defeat.
The winners will face either Costa Rica or Greece in the quarter-finals and either side would fancy their chances of reaching the last four of the competition.