Papajohn was born and raised Vestavia Hills, a suburb of Birmingham, Alabama, to a Greek American family. He graduated from Vestavia Hills High School in 1983 and went on to play for two years at Gulf Coast Community College in Panama City, Florida. He was drafted by the Texas Rangers in the 1985 Major League Baseball Draft. Instead of signing a contract, he accepted a baseball scholarship to Louisiana State University in Baton Rouge, Louisiana.

Nicknamed Poppy, Papajohn was an outfielder for Skip Bertman's LSU Tigers. He was a member of the 1986 SEC Baseball Tournament All-Tournament Team and he, along with teammates Mark Guthrie, Joey Belle, Jeff Reboulet, Jeff Yurtin, Jack Voigt and Barry Manuel, among others, helped LSU make its first College World Series appearance in 1986. Papajohn helped lay the foundation for success at LSU, as Future LSU teams would go on to win six national championship from 1991-2000, 2009.

Papajohn got his start in acting while he was a student at Louisiana State University. Already an athlete, he was hired to be a stunt performer in the film Everybody's All-American which was being filmed on the campus of LSU and featured football action sequences filmed during LSU football games in Tiger Stadium. From there he moved on to being a stunt performer in films such as Money Talks and Starship Troopers and acting in films like Predator 2, For Love of the Game, where he plays New York Yankees slugger Sam Tuttle, and Spider-Man and Spider-Man 3, in which he plays Dennis Carradine, the thief that was thought to have killed Uncle Ben; Papajohn also makes a cameo appearance as a different character in the film series' reboot, The Amazing Spider-Man. He has also starred in Terminator 3: Rise of the Machines, Transformers: Revenge of the Fallen, Terminator Salvation, Land of the Lost, and G-Force in 2009.