Chandler was drafted out of the University of Florida in the 1978 NFL Draft by the New Orleans Saints. During his career with the Gators, he caught 92 passes for 1,963 yards and a school record 22 touchdowns, and added six more scores rushing and returning kickoffs. He was a College Football All-America Team selection in 1976 and 1977.
After college, Chandler was drafted by the New Orleans Saints with the third overall selection in the 1978 NFL Draft. Chandler was selected to the Pro Bowl after his second season in the league after finishing with 1,069 yards and 6 touchdown receptions. He was traded to the San Diego Chargers in 1981 to replace star receiver John Jefferson who was traded to the Green Bay Packers after a bitter contract hold-out. He led the NFL in receiving yards (1,032) and receiving touchdowns (9) for the strike-shortened 1982 season. His 129 yards receiving per game that year is still an NFL record . Chandler completed his career with the San Francisco 49ers in 1988. One of his more notable performances was in a _San_Diego_Chargers_41.2C_Miami_Dolphins_38_.28OT.29 game known as The Epic In Miami, where he caught six passes for 106 yards and returned a punt 56 yards for a touchdown in the Chargers 41-38 victory. He also caught nine passes for 124 yards in a playoff win over the Pittsburgh Steelers in the following season.
Chandler retired from the NFL during the 1988 season after an 11 year playing career. During his NFL career, he caught 559 passes for 8,966 yards and 56 touchdowns, rushed for 84 yards, returned 48 kickoffs for 1,048 yards, and gained 428 yards on 67 punt returns. Overall, he amassed 10,526 all-purpose yards. At the time of his retirement, Chandler ranked 12th in NFL history in receiving yards and 13th in receptions. He also earned four Pro Bowl selections, including three with the San Diego Chargers. In 2001, Chandler was inducted into the San Diego Charger Hall of Fame.
Chandler eventually went to Dallas after seven years coaching in NFL Europe, including a stint as head coach of the Berlin Thunder in 1999. Before that, he also coached at the University of Central Florida and Father Lopez Catholic High School in Daytona Beach, Florida.
Chandler has established a scholarship fund for minority students through the Wes Chandler Celebrity Golf Classic.
Minneapolis avant-garde jazz trio Happy Apple has a song from their album "Please Refrain from Fronting" titled "Take Wes Chandler For Instance."
Ralph Macchio's character in The Karate Kid (Daniel Larusso) wore the number 89 San Diego Chargers jersey (Chandler's number at the time) during several scenes of the movie.