The 22-year-old suffered anterior cruciate ligament damage in a tackle by Castleford's Rangi Chase as the Warriors lost 36-22 on Friday.
Manfredi had been a regular for Wigan, who are third in the table, this season, scoring 15 tries in 25 games.
"I'm really gutted for him, he's a great player," said coach Shaun Wane.
"It's really sad but we've got a great medical department here and I'm sure he will bounce back stronger from it.
"The players are really motivated to get something from the season for him."
Wigan Warriors winger Dom Manfredi has been ruled out for the rest of the Super League season with a long-term knee injury.