Both men, who trained with the group on Thursday, were shown to have contracted Covid-19 after tests in the last 24 hours.
The two unnamed players must now isolate for 10 days as per Government rules, keeping them out of the game at St James’ Park, a Europa Conference League match against Vitesse Arnhem and the London derby at West Ham next weekend.
Both players are due to be retested on Saturday, as per standard procedure.
The club are understood to be confident that no other players will have to isolate having come into close contact.
In his press conference on Friday afternoon, Spurs boss Nuno Espirito Santo admitted that he has been left with “huge issues” following the latest international break.
The news will bring more frustration for Nuno, who saw his side suffer in the wake of September’s international fixtures when some squad members returned injured and three South American players went to Croatia for 10 days in order to avoid hard quarantine in England.
Spurs signed off before the international break with a 2-1 win against Aston Villa.
Nuno said earlier on Friday: “After the international break there are always huge issues that happen. We have problems but I will not say before the game.”
After that win over Villa, Nuno was hoping to name an unchanged side. However, those plans have been hit.
The Portuguese said: “What we wanted was after the game against Villa, which I think was one of the best performances that we had in terms of the team, how we did things, how we reacted when we conceded, all these small steps that we took in the right direction, the ideal was to immediately have a good week, try to establish and create routines among players.
“That was not possible. So you stay here with a group of players, with the small numbers, just try and improve them individually. Not in the aspect of the team because the squad was not here. So what we want now is try to recover them.
“We have problems and you’re going to see that we have problems. We have small issues, big issues if you want.
“But the best way is to get a reference point and the reference point was the game against Villa. So that should be our starting point for a tight schedule that we’re going to be four games away from home.
“So starting from there, if we could, I’ll be honest with you, we would repeat the same XI, because that’s the best way to start something. It will not be possible but then you have to try again, try again, try again.
“This is football. We are used to it. The players go to national teams. When they go what we want is for them to return healthy.
“We know that each moment it is becoming harder for them. The schedule, the demands of club and national teams are really, really high and demanding on the players.
“But we cannot avoid it. We all expect and there has been a lot of dialogue and speculation about it – something has to be done so the players don’t spend so much time away from the clubs.”