Wayne went down during the fourth quarter of the Colts' 39-33 win over the Denver Broncos Sunday while trying to make a catch from Andrew Luck.
Pagano said an examination revealed the 34-year-old Wayne had torn the anterior cruciate ligament of his right knee.
"He'll get his surgery, he'll rehab, he'll grind," he said. "He'll do whatever it takes to get back on that field. He's not going out like this."
A six-time Pro Bowl selection, Wayne had the longest active streak in the NFL with 189 straight games played. He was leading the team with 38 catches for 503 yards over seven games this season.
The 13-year Colts veteran has 1,006 career receptions for 13,566 yards with 80 touchdowns.
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