Clayton is leaving to "pursue other interests and spend more time with his family," according to a statement released Wednesday by the Stampeders.
"I'm looking forward to spending more time with my wife Kerry, my two grown children and my four grandchildren as well as continuing with my private orthopedic practice," Clayton said in the release.
Clayton was an athletic therapist for the Winnipeg Blue Bombers prior to joining Calgary and has worked in the CFL as a medical professional for 36 years.
The Stampeders won four Grey Cups during Clayton's years with the club.
"I can’t overstate the value of Pat’s hard work and dedication and his contributions to the success of the football club," Stampeders head coach and general manager John Hufnagel said.
"He will be missed and I wish him all the best as he begins a new chapter in his life."