During his nine-season NFL career, Mitchell played for the Baltimore Colts, San Diego Chargers and Los Angeles Rams.

The first Colt in franchise history to gain 1,000 yards in a single season, Mitchell achieved the feat three times, as well as leading the NFL in receptions in 1974 and 1977.

[2] As a junior, Mitchell was injured in the middle of the season, but still managed to earn an All-South Jersey team honorable mention.

He and Franco Harris joined the varsity squad, and contributed to Penn State's second consecutive undefeated 11–0 season.

The Nittany Lions finished at #2 in the AP poll, and earned a spot in the 1970 Orange Bowl where they defeated #6 Missouri 10–3.

[6] Mitchell split time at running back with Harris and senior Charlie Pittman, but still recorded 113 carries for 616 yards and six touchdowns on the season.

Mitchell suffered a leg injury the following week against Boston College, which forced him to miss the Nittany Lions' loss to Syracuse.

[9] Penn State won their remaining five games of the season, finishing with a 7–3 record and a #20 ranking in the AP poll.

[12] In week three, Penn State almost lost in an upset to Air Force before a late game field goal gave them the 16–14 victory.

For Mitchell, this game cemented his All-America status and brought him to the forefront of the Heisman Trophy watchlist.

During the game, Mitchell broke six Penn State records, including career rushing yards (passing Lenny Moore), single-season rushing yards (also passing Moore), most points in a season, most career points, and extended his single-season touchdown mark.

[21] Despite the loss to Tennessee, Penn State earned a bid to the 1972 Cotton Bowl where the #10 Nittany Lions faced #12 Texas.

His ability to break free as a runner and his versatility as a pass catcher made him a dual threat on offense.

Mitchell, along with teammate Bert Jones, propelled the Baltimore Colts to three consecutive AFC East Division titles, unseating a powerhouse Miami Dolphins team that had won back-to-back Super Bowls and topped the division for four straight years (1971–74).

[26] In 1973, the Colts refreshed their roster with younger players and brought in rookie quarterback Bert Jones.

His 13 receptions secured his NFL lead in the category and broke the Colts' single-game record, previously held by Raymond Berry.

[25] In week six, Mitchell recorded his career-high rushing performance with 26 carries for 178 yards and one touchdown against the Kansas City Chiefs.

Mitchell and the Colts faced his former Penn State teammate Franco Harris and the Pittsburgh Steelers in the first round of the 1975-76 NFL playoffs, losing 10–28.

[36] Baltimore went 11–3 in the regular season and earned a rematch against the Pittsburgh Steelers in the Divisional Round of the 1976-77 NFL playoffs.

Mitchell also led the NFL in receptions for the second time in his career, with 71 catches for a career-high 620 yards and four receiving touchdowns.

The Colts granted his request, trading him to the San Diego Chargers on August 23, 1978, for running back Joe Washington and a 1979 fifth-round draft selection (this became the 131st overall pick–traded to the Detroit Lions for Greg Landry).

As of the 2023 NFL season, Mitchell is ranked second in Colts career rushing yards behind Edgerrin James.

[25] Mitchell had a slow start to the season before turning in his best performance in week seven against the Miami Dolphins, where he accounted for all Chargers scoring.

[47] The next week against the Detroit Lions, Mitchell caught a 55-yard touchdown pass from Fouts and added 53 yards rushing on nine carries.

After starting the season at 1–3, the Chargers fired head coach Tommy Prothro and replaced him with Don Coryell.

Williams' rise, coupled with Coryell's vaunted passing offense, led to limited production from Mitchell throughout the 1979 season.

[25] Meanwhile, Fouts had the best season of his career to-date, leading the league in passing yards (4,082) and earning All-Pro and Pro Bowl selections.

[51] The Chargers released Mitchell on August 26, 1980, as part of the final round of roster cuts in the lead-up to the 1980 NFL season.

[55] Mitchell and former Pittsburgh Steelers great Franco Harris, his friend and former Penn State teammate, started Super Bakery, a company that produces nutrition-oriented foods for schoolchildren.

He and Harris also partnered to rescue the Parks Sausage Company in Baltimore, the first black American owned business in the U.S. to go public.