Despite his skill and adaptability, Wilson was not drafted until the 7th round of the 1960 NFL Draft by the St. Louis Cardinals. After originally playing as a cornerback, Wilson switched to free safety, and it was here that he found his place on the team.
Not long after Wilson made the team, Defensive coordinatorChuck Drulis crafted a play that called for the free safety to take part in a blitz. The play was code-named "Wildcat", after Wilson's nickname. When the Cardinals first ran the safety blitz, the pressure was severe since most teams didn't (and still don't) expect a defensive back to take part in a pass rush. This single play also helped to set up today's defenses where a blitz can come from anywhere.
Wilson eventually made All-Pro honors eight times in his career. Wilson represented the Cardinals on eight Pro Bowl teams. During the 1966 NFL season, Wilson had at least one interception in seven consecutive games, en route to a 10-pick season that led his league. Jerry Kramer, a guard for the Green Bay Packers and author of Instant Replay, called Wilson "the finest football player in the NFL." Kramer described Wilson's play during an October 30, 1967 game, "...he fired up their whole team ... (h)is enthusiasm was infectious." Wilson is renowned for not only playing, but intercepting a pass, with casts on both hands due to broken wrists. On the September 18, 2006 edition of SportsCenter, Mike Ditka challenged Terrell Owens' toughness by not playing for 2–4 weeks due to a broken finger. He cited Wilson's interception with casts on both hands as proof of a tougher football player. He ended his career with 52 career picks for 800 yards and five touchdowns.
Wilson served as the Cardinals' interim head coach in 1979 after the dismissal of Bud Wilkinson, and was the franchise's general manager from 1980 through 1993.
Wilson was inducted into the Pro Football Hall of Fame in 1978. In 1999, he was ranked number 43 on The Sporting News' list of the 100 Greatest Football Players, making him the highest-ranked player to have played a majority of his career with the Cardinal franchise. The team has also retired his uniform number 8. He was ranked #9 on NFL Network's list of the "Top 10 Draft Steals" in NFL history.