The 31-year-old Brazilian – snapped up from Olympique Lyonnais earlier this summer – limped off just seven minutes into the 3-1 defeat to Manchester City last Monday.
He has not trained since either, with Nuno revealing ahead of the trip to the London Stadium: "He's one of the issues that we have.
"I'm not very confident he will be available for this game."
When asked if Marcal's injury is perhaps a worry for the Molineux clash with Fulham a week on Sunday as well, Nuno added: "It all depends on how the player gets better but now, he's not training. He's on treatment.
"We've had a diagnosis and it's an injury to his calf. Let's keep on trying to treat him and, hopefully, he can get better and be available."
Ruben Vinagre came on for Marcal against City and appears the most likely to feature in his absence against the Hammers.
Some fans are calling for new signings Nelson Semedo and Ki-Jana Hoever to both play, though, with one of those right-wing-backs moving over to the left flank.
On Semedo, Nuno added: "We're bringing in a high-quality player, a player who has played at the highest level of European football.
"He's a good character and has integrated very well. We're very happy to have him."