A native of Charlotte, North Carolina, Humphries attended Mallard Creek High School, where he was a three-sport athlete in football, basketball, and track.

He was an All-American offensive lineman, clearing the way for 2,000-yard rusher Jela Duncan, and helping protect quarterback Marquise Williams.

In 2011, Humphries helped Mallard Creek to a 13–1 record and berth in the NCHSAA Class 4AA State Semifinals, where they were upset 41–27 by Greensboro (NC) Page.

[4] Recruited by virtually every Division I program in the country, Humphries chose Florida over offers from Alabama, Georgia, and North Carolina, among others.

Humphries was named First-team Offense Southeastern Conference Coaches' All-Freshman (OL) and Sporting News Freshman All-American.

After his junior season, Humphries entered the 2015 NFL draft, and was selected with the 24th overall pick by the Arizona Cardinals.

Head coach Bruce Arians nicknamed him "knee-deep", explaining that you need to keep "A knee in his ass every day" to keep him motivated.

[11] He started his rookie season as the Cardinals' third right tackle on their depth chart, behind veterans Earl Watford and Bobby Massie.

He had his professional debut and first career start in the Cardinals' season opening 23–21 loss to the New England Patriots.