Due to take on Leyton Orient in the Carabao Cup on Tuesday, the game was unfortunately called off after a number of the League Two side tested positive for Covid-19.
It means a host of players on the fringes of the first team will be desperate for minutes and Mourinho has some big calls to make as he looks to avoid a European upset.
But who should the boss select against the North Macedonian side?
We’ve asked our Tottenham writers and fans at football.london to give their thoughts on who should be in the XI. Here is what they had to say:
Alasdair Gold – Tottenham Hotspur correspondent
The called off Orient match changes plenty and Mourinho will now have a nearly full squad of pretty much refreshed players to choose from.
That makes it even harder to predict his starting XI though because beforehand it would have simply been all of the players who didn’t start at Orient.
Now Mourinho has to take only the Newcastle match into account on Sunday.
He will have to decide whether to transfer many of the players who were set to play on Tuesday into the starting line-up in Macedonia.
Alli was left out of the trip to Bulgaria last week but was set to play against Orient and ultimately for Mourinho it’s about whether he wants to give minutes to those who need them or look to continue to improve the fitness of his regular starters.
He could give Giovani Lo Celso and Tanguy Ndombele another split shift in the number 10 role and Reguilon can be registered for the match to make his debut if another player is removed from Tottenham’s Europa League squad.
Gold’s team: Hart; Aurier, Alderweireld, Sanchez, Reguilon; Sissoko; Hojbjerg; Lamela, Lo Celso, Bergwijn; Kane.
Rob Guest – Tottenham reporter
The cancellation of Tuesday’s game against Leyton Orient means a number of players due to play in the Carabao Cup match need to be given minutes.
It represents the perfect chance for Mourinho to hand some of his side a breather ahead of the Newcastle game as he can still put out a very strong starting XI.
Aurier should come in as he hasn’t played since the new season kicked off, with Lamela also given a first start as he was due to be in the team against Orient.
It will probably be one of Ndombele or Lo Celso to start as they are both not yet fully fit, while Alli may come back into the head coach’s thinking following his recent absence.
Ben Davies could do with a rest and new signing Sergio Reguilon may replace him in the side providing of course that they decide to register him for the Shkendija game.
Guest’s team: Lloris; Aurier, Alderweireld, Sanchez, Reguilon; Sissoko, Ndombele; Lamela, Alli, Bergwijn; Kane.
Lee Wilmot – Head of Football for London and the South and Tottenham fan
Mourinho showed no sign of wanting to field a weakened team against Plovdiv in the last round and I see no reason why he would do so this time around, even if I would give a few fringe stars a go.
I, personally, would leave Dele Alli out again. To really get back into his stride I think he should be unleashed in the Premier League next weekend. I’m not convinced his personality is suited to showing what he is capable of against Shkendija.
The lack of Carabao Cup game makes things a bit easier for Mourinho.
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Hugo Lloris should play in goal with a back-line of Serge Aurier, Eric Dier, Davinson Sanchez and Ben Davies – like Alli I’d wait to unleash Sergio Reguilon in the Premier League.
Tanguy Ndombele should start again, alongside Giovani Lo Celso and Moussa Sissoko, with Son Heung-min, Erik Lamela and Harry Kane up front.
Wilmot’s team: Lloris; Aurier, Dier, Sanchez, Davies; Ndombele, Sissoko, Lo Celso, Son, Bergwijn; Kane