Humphrey was born in Maryville, Tennessee in 1984. He attended Maryville High School, where he played high school basketball for the Maryville Rebels. As a senior, he was named Tennessee's Class AAA Mr. Basketball for the 2002–03 season after averaging 27.6 points, 8.0 rebounds and 7.0 assists.
Humphrey accepted an athletic scholarship to attend the University of Florida in Gainesville, Florida, and he played for coach Billy Donovan's Florida Gators men's basketball team from 2003 to 2007. He emerged as a prolific weapon from outside the arc during the 2005–06 season in which he hit several clutch three-pointers, including three in the Final Four against George Mason and the championship game against UCLA. The 73–57 win over UCLA was the clincher of Florida's first national basketball championship. The Gators finished the season with a 33–6 mark.
Humphrey's dominance continued during the 2006–07 campaign and with the other members of the starting five returning, the Gators rolled to a 35–5 record. On March 23, 2007 in the St. Louis regional NCAA tournament game against the Oregon Ducks, the game was delayed 10 minutes after a three-point shot Humphrey made damaged the net. During the 2007 Final Four, he hit four three point shots in his team's 76–66 victory against UCLA in becoming the record holder for most three pointers made during the NCAA tournament, surpassing former Duke star Bobby Hurley. On April 2, 2007 he won a second NCAA basketball championship with the Florida Gators, scoring 14 points in an 84–75 victory over the Ohio State Buckeyes. This win established Florida as the first team to repeat as NCAA basketball champions since Duke, in 1991 and 1992.
Humphrey was also a proven academic success, becoming just the second Gators basketball player to be named a first-team Academic All-American. Humphrey also served as the President of the Fellowship of Christian Athletes Chapter at the University of Florida. He graduated from the university with a bachelor of science degree in applied physiology and kinesiology in 2007.
On June 30, 2007, Humphrey accepted an offer from the Washington Wizards to participate in their summer league but was cut. He then crossed the Atlantic, signing on with PAOK, one of Greece's best-known club teams. When the team signed a third American player, Humphrey was cut due to league rules that limit team rosters to two American players. He spent the second half of the 2007–2008 season in Poland playing for Energa Czarni, but saw limited minutes. In July 2008, Humphrey signed a one-year contract with Ratiopharm Ulm, a south German team playing in the Basketball Bundesliga (first German division). After spending the 2011–12 season in the NBA Developmental League, he signed with Denain of France's second-tier league. On December 27, 2014 he signed with BC Juventus of the Lithuanian League. On January 7, 2015 he left Juventus due to back issues. He played 2 games averaging 6 points.