Newcastle's visit to Aston Villa, scheduled for Friday, became the first Premier League match to be postponed due to a coronavirus outbreak since play resumed in June, the league confirmed on Tuesday.
Several Newcastle players and staff have tested positive for coronavirus, leading the club to shut their training ground.
"Newcastle lodged a request with the Premier League to rearrange the game following a significant increase in Covid-19 cases at the club, which resulted in Public Health England North East advising that their training facilities remain closed," the Premier League said in a statement.
"The Premier League Board agreed, as a consequence, that the club are unable to train and adequately and safely prepare for their match on Friday."
Newcastle manager Steve Bruce had already cancelled training on Sunday after four players and a member of the backroom staff tested positive for the virus last week.
Bruce was already without five first-team players for last Friday's 2-0 win over Crystal Palace.
In a statement, Newcastle said: "Several Newcastle United players and staff members are now self-isolating at home after returning positive test results in recent days and the club's training centre site has been temporarily closed in order to contain the spread of the virus."
No Premier League match had previously been called off since football resumed after a three-month stoppage between March and June, but the decision was backed by Villa.
"Aston Villa can confirm that the club fully supports the Premier League's decision to postpone our fixture with Newcastle United on Friday following a significant Covid outbreak at the Tyneside club and the shutdown of their training ground by Public Health England," Villa said in a statement.
"Everybody at Aston Villa wishes a speedy recovery to all those @NUFC affected by the virus."
Neither side are involved in European football, meaning there is plenty of space in the calendar for the match to be rescheduled despite a shortened season.
The city of Newcastle will enter the most severe tier-three restriction band when the latest national lockdown in England ends on Wednesday.