For Friday's FA Cup third round match against Crystal Palace at Molineux, he is without defenders Willy Boly, Fernando Marcal and Jonny Castro Otto, he is without forwards Daniel Podence and Raul Jimenez, and midfielder Leander Dendoncker's availability will be assessed on the day.
This long list of absentees, and the likely resting of other key starters, will mean opportunities to enter the starting XI for players who regularly find themselves on the bench.
It could also serve as a reintroduction for Morgan Gibbs-White and Patrick Cutrone, recently recalled from loan stints at Swansea City and ACF Fiorentina, to enable them to quickly reintegrate into Wolves' severely injury-hit Premier League starting XI.
With four league matches still to play on top of his side's 2-0 victory over Sheffield United on Saturday and this relatively unimportant cup fixture, Palace boss Roy Hodgson is expected to make multiple changes to his starting line-up.
Palace will stick with their tried and tested 4-4-2 formation - there is nothing special about it tactically, but it works for them, and they have no reason to deviate from it. Their attacks will come primarily down the wings, with the dribbling ability of Jordan Ayew and Eberechi Eze key to their forward progression of the ball.
On the injury front, Palace are not having much more luck than Wolves. Centre-backs Scott Dann and Gary Cahill and left-flank utility man Jeffrey Schlupp are all injured, with captain Luka Milivojevic doubtful due to a back spasm suffered in training.
Despite transfer speculation linking him to Dutch giants Ajax, left-back Patrick van Aanholt can be expected to start. An absence from the squad could be an indicator of a deal being negotiated.
Tactics and formation
Knowing that his side should beat Palace given Hodgson's upcoming schedule and injury concerns, Nuno will likely send out a very attack-minded starting line-up. A 4-2-3-1 is likely to start, to give Wolves as many creative options as possible for when Palace sit back and defend.
As is standard for cup games in which the opposition carries a limited attacking threat, John Ruddy will start in goal, as confirmed by Nuno on Thursday.
A back four of Ki-Jana Hoever, Conor Coady, Max Kilman and Rayan Ait-Nouri seems probable - Ait-Nouri will likely play as a wing-back, pushing very high up the pitch to attack the Palace box as he looks to score his second Wolves goal against the opposition that conceded his first, on his debut.
With Ait-Nouri pushing high, the other three defenders can shift into a familiar back three, with Coady moving central as Kilman shifts left and Hoever tucks in on the right.
Wolves' two central midfielders will likely be Ruben Neves and Owen Otasowie. Surrounded by a team of primarily young players, Neves will be trusted to run the game and take a leadership role. Otasowie should play the Dendoncker role, as the enforcer and bodyguard alongside the Portuguese regista, while making high runs towards the box in support of the forwards.
Dendoncker, still recovering from a bone bruise picked up on international duty with Belgium, should be able to make an appearance from the bench as he works his way back to full fitness.
Adama Traore should start on the right of the three. He finally got his season off the ground with an assist and a smart run to earn a penalty away at Brighton and Hove Albion, and he now needs a run of starts and good performances to fully build up his confidence.
Meanwhile, Pedro Neto, arguably Wolves' most consistent attacking performer this season, should start on the left.
The two central attackers will capture the attention of most Wolves fans. Wolves academy graduate Gibbs-White seriously impressed Swans supporters during his injury-limited game time during his loan spell, and he has recovered from a foot injury picked up while there.
He is expected to be able to start, with the cup tie providing him with the perfect opportunity to get used to his new and old team-mates as he plays in the no. 10 role in place of the injured Daniel Podence. Vitinha might see some game time in the closing minutes of the game, as Nuno will be cautious of aggravating any potential remaining foot problems.
"Hi guys, the pasta merchant is back"
Those were the words which greeted Wolves fans on Instagram this morning as Cutrone confirmed his return to Molineux. As a much more direct and physical striker than his younger counterpart Fabio Silva, Cutrone will play a poacher's role, working on the shoulder of the last defender to get in the box fast and attack the crosses from Traore and Neto, while he can also look for the through ball from Gibbs-White or Vitinha - his energetic running never failed to impress during his first stint at Molineux.
Cutrone is far less focused on build-up play than Silva, so his increased likelihood of converting a chance will likely mean the central attacking midfielder having to stay central and play a much more active role in pulling the strings of the attack.
However, Cutrone's return isn't yet confirmed - Wolves are awaiting confirmation that he has received international authorisation clearing him to play against Palace.
If his authorisation is not received in time, Silva will almost certainly play, giving Gibbs-White more license to push forward against the defensive line.
Predicted line-up: 4-2-3-1:
Ruddy; Hoever, Coady, Kilman, Ait-Nouri; Neves, Otasowie; Traore, Gibbs-White, Neto; Cutrone.
It is unlikely that Palace will play with full intensity, given that they are sat in 14th position in the league, with three teams below them having games in hand which could see them quickly catch up.
Hodgson's weakened team will largely have to sit back and defend against a Wolves side which will spend most of the game pressing them in their own half.
This should lead to a high number of corners as Wolves try to find a way through, with Palace's best-attacking opportunities likely to come via fast, dribble-based counterattacking movements.
Ruddy, without an appearance to his name in months, cannot be expected to keep a clean sheet.
Wolves will likely progress to the next round, with 2-1 a probable score-line.