The unnamed stars trained with the team on Thursday before the positive results were confirmed - and will miss the Sunday afternoon clash.
As per standard procedure, they will be retested on Saturday with no other players reportedly coming into close contact with the duo.
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.
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.
This time around, the club had been boosted by the news that Giovani Lo Celso and Cristian Romero did not need to quarantine on their return from Argentina duty. Colombian defender Davinson Sanchez and Brazilian Emerson Royal were due to spend their allotted period at the club’s Hotspur Way base.
Spurs were planning to fly the four players back via private jet immediately after their games to make a call on whether they are able to face Newcastle once they were back in the country. There is currently nothing to suggest any of the quartet are the two to have tested positive.
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.”
Additional reporting by PA Media.