The 26-year-old, drafted to Indianapolis in 2012, is now contracted to the Colts until the end of the 2021 season.
Luck's wages take him above the annual average of $22.1m collected by Joe Flacco of the Baltimore Ravens, the previous record earner.
"I am thrilled and excited," Luck said.
The Colts made the play-offs in Luck's first three seasons with them but he suffered an injury-hit 2015, missing two early matches with a shoulder problem before suffering a lacerated kidney that ruled him out after week nine.
Colts owner Jim Irsay said: "This is an exciting day for the organisation and Colts fans around the globe.
"Andrew is the consummate professional, possesses extraordinary talent and is our leader on and off the field."
Indianapolis Colts quarterback Andrew Luck has signed a new six-year deal worth $140m (£104m) to become the highest-earning player in NFL history.