Matt Ritchie scored in the 65th minute as the Magpies moved clear of the relegation zone with a 1-0 victory.
Mourinho has now managed more away Premier League matches against Newcastle without a victory than any other opponent, having recorded four defeats and three draws in seven fixtures.
While the Red Devils boss has won a pair of League Cup matches at St James' Park, in November 2004 and December 2006 with Chelsea, he remains winless in league play.
It was the second straight defeat away from home for United, who also dropped a 2-0 result to Tottenham on January 31 at Wembley Stadium.
Newcastle, meanwhile, have lost just one league match in their last seven, having recorded two wins and four draws in that span to rise to 13th in the table. The lone defeat came in a 3-1 loss to runaway league leaders Manchester City on January 20.
The result also strengthened Rafael Benitez's record against Mourinho, who has now lost six times against the Spaniard in all competitions — second only to Pep Guardiola's nine victories versus the Portuguese.
Chances were hard to come by on Sunday, though Anthony Martial and Alexis Sanchez spurned golden opportunities and Romelu Lukaku had a goal disallowed for United.
The Magpies have proved to be stiff opposition for new Manchester United signing Sanchez, who went the full 90 minutes in his third league match since joining the club from Arsenal in January.
Having now shut out Sanchez through five matches, Newcastle remain the only Premier League side the Chile international has faced more than twice without scoring.
Sanchez now has one goal through four matches in all competitions for United.
The defeat saw second-place United remain 16 points behind rivals Man City at the top of the table, with Tottenham just four points back of the Red Devils in third.
The Red Devils don't resume league play until February 25, when Mourinho faces his former club Chelsea.