Humphrey played football, basketball, ran the low hurdles and excelled in the shot put in high school.

Tennesse State was twice HBCU national champion with Humphrey, winning the Grantland Rice Bowl in 1965 and 1966; while achieving an overall 35–3–1 record during his tenure.

[14][4][15] Even after an excellent rookie season, Humphrey knew he had to expand his technique and skill set to continue his success in the NFL.

He credited the Falcons' new 1969 defensive coordinator, Marion Campbell, with helping him branch out to obtain that knowledge, leading to his continued success.

[13] In 1969, he had 10 or 10.5 sacks, without any signs of a "sophomore slump"; being named second-team All-Pro by the AP and Newspaper Enterprise Association (NEA).

[2] He later decided to return to football, and in 1979, the Falcons traded him to the Eagles for two fourth-round draft picks.

[15] In 1980, Humphrey was a designated pass rusher, recording a team-high 14½[6][18] or 15½ sacks (career high)[19][1] helping the Eagles become NFC champions and earn a spot in Super Bowl XV.

[20] During Super Bowl XV, when Humphrey was called for roughing the passer against Oakland Raiders quarterback Jim Plunkett, he picked up the penalty flag and fired it back at referee Ben Dreith.

[34] In February 2014, Claude Humphrey was elected to the Pro Football Hall of Fame on the senior ballot.

[35] On August 2, 2014, Humphrey was officially inducted at the Enshrinement Ceremony where his bust, sculpted by Scott Myers, was unveiled.

[6][41] The Professional Football Researchers Association named Humphrey to the PFRA Hall of Very Good Class of 2009.

[1] Humphrey also had a guest appearance on The Dukes of Hazzard episode "Repo Men" in which he portrayed Big John, a counterfeiter.