Irsay, who has dabbled with splashy hires like Sean Payton or Jim Harbaugh in recent years, may be of the mindset that he needs a bigger name to help push this franchise back in the right direction (and help sell some tickets at a time when Luck's murky future clouds everything else in the franchise).
Pagano has been the head coach of the Colts since the 2012 season.
The Colts made the move about an hour after Sunday's 22-13 win over the Texans.
But Luck, in his first public comments Friday in months, attempted to restore hope and said he doesn't anticipate requiring another procedure, and the Colts have an up-and-comer GM in Ballard and established, never mind eccentric, owner in Irsay. Ballard has strong ties to two members of the Chiefs coaching staff, who he worked with prior to getting the job in Indianapolis last season, both of whom are expected to merit consideration for the coaching job.
Said Irsay: "Chuck's first season was one of the more inspirational stories in National Football League history as he courageously battled and overcame leukemia. We are thankful for Chuck's contributions to our franchise and community and we wish him, Tina and the entire Pagano family nothing but the best moving forward".More news: Texas woman allegedly damages Warhol paintings on first date
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Pagano's career with the Colts began in 2012, his first of three consecutive 11-5 playoff campaigns.
Pagano's firing will be first and foremost the result of a defensive-minded coach's inability to coax even adequate play from that side of the ball for the vast majority of his six-year tenure.
And like Caldwell's final season, sabotaged by Peyton Manning's neck injury, Pagano's was marred by the absence of Andrew Luck all year following shoulder surgery.
Irsay fired general manager Ryan Grigson past year, but kept Pagano at the time.
While many have speculated the Giants will take a quarterback at No. 2 overall, newly hired general manager Dave Gettleman would not commit to that. Chiefs offensive coordinator Matt Nagy and Seahawks offensive line coach Tom Cable have been reported to be possible replacements for Pagano.