The Pakistan white-ball international, making his Rapids debut as short-term cover for the incoming Mitchell Santner, bamboozled the home batters to finish with figures of 3-21.
Willey, who rejoined the Steelbacks after a seven-year stint at Yorkshire and was recently appointed T20 captain, looked set to lead his side to victory with 36 from 24 balls as they chased Worcestershire’s total of 196 for nine.
But Mir’s introduction triggered a Northamptonshire collapse as five wickets tumbled for 26 and fellow leg-spinner Brett D’Oliveira chipped in with 3-28 to restrict the hosts to 181-8.
Worcestershire, who finished bottom of the North Group last season with just two wins, won the toss and batted but were soon in trouble as Tom Taylor (3-42) removed openers Michael Bracewell and D’Oliveira in the powerplay.
Jack Haynes began the rebuilding job, finding the boundary regularly in his 27 from 17, but he and Kashif Ali (16 from 12) were both caught in the deep off miscued shots and it was left to Adam Hose to underpin the innings with a knock of 61 from 40.
Ed Pollock maintained momentum, clubbing Taylor for two sixes in his 23 from 11 and Mir slammed an unbeaten 20 from only seven balls.
Northamptonshire looked comfortable at 90-1, but then Mir took centre stage and the pendulum swung towards the visitors.