Winger Wainwright is on his way to Championship side Dewsbury for the 2011 season having scored 40 tries in 104 appearances for the Tigers since his move from Batley in 2007.
Prop Higgins has made 105 appearances since moving from Hull while Clayton has had two spells at the club, with two years at Huddersfield and Salford in between.
All three players starred in their National League 1 Grand Final win over Widnes in 2007.
Tigers boss Terry Matterson said: “I’d like to thank Michael, Liam and Ryan for their terrific service for the club over the past four years. They joined us just after we were relegated in 2006 and played important roles in gaining promotion the following year.
“In the past three seasons in Super League they have been integral members of our squad and I’m grateful for their efforts since they have been here. I’d like to wish them all the best for the future.”
The trio join Michael Shenton and Mitchell Sargent in leaving The Jungle, and so far the club have already announced the signings of Richie Mathers (Warrington), Danny Orr (Harlequins) and Nick Youngquest (Crusaders) for next season.