He played college football for the Penn State Nittany Lions, where he set several school records for his offensive production over three seasons before forgoing his senior year to enter the NFL.

A free agent following the 2023 season, Barkley signed a three-year deal with the Eagles, setting numerous franchise records and rushing for over 2,000 yards in his first season with the team, along with helping Philadelphia win Super Bowl LIX and being named AP NFL Offensive Player of the Year.

During the team's Super Bowl LIX win, Barkley broke the record for most rushing yards in one season, previously held by Terrell Davis.

[3] In 2001, Barkley and his family moved to Bethlehem, Pennsylvania, in the Lehigh Valley, in search of a safer and more suburban environment.

[5] Barkley attended Whitehall High School in Whitehall Township, Pennsylvania, which competes in the Eastern Pennsylvania Conference, an elite division of large high schools in the Lehigh Valley and Poconos known nationally for producing a large number of NFL and other professional athletes.

[11] Later in the track and field season, Barkley set personal best marks of 46'2.5" (14.08m) in the shot put and 6'0" (1.83m) in the high jump.

However, quarterback Trace McSorley threw an interception in the Pitt end zone with 1:41 left that denied the Nittany Lions' hopes of completing the comeback.

[28] On November 1, 2016, Barkley was named a semi-finalist for the Maxwell Award, granted to the all-around best collegiate football player of the year.

His efforts helped Penn State recover from a 28–7 deficit to stun Wisconsin, 38–31, in the 2016 Big Ten Championship Game.

This made Barkley the first player in Big Ten history to record a return and passing touchdown in the same game.

By late February 2018, some mock drafts projected him as high as the second selection overall,[65] the highest for a running back since Reggie Bush in 2006.

ESPN analyst Mel Kiper Jr., who has history of not supporting the selection of running backs in the NFL draft's first round, said "Barkley is a once in a lifetime talent; teams that pass on this young man will be sorry.

[67] According to NFL analyst Ian Rapoport, the Cleveland Browns were "strongly considering" drafting Barkley first overall, which would have made him the first running back since Ki-Jana Carter in 1995–also of Penn State—to be selected first overall.

[86] In recognition of his rookie season accomplishments, Barkley was elected to the 2019 Pro Bowl, where he helped the NFC win the Skills Showdown.

[102] In Week 17 against the Eagles, Barkley rushed 17 times for 92 yards, including a season-long 68-yard run that resulted in a touchdown, during the Giants' 34–17 loss to Philadelphia.

[106] During the following week's 17–13 loss to the Bears, Barkley was carted off the field after suffering a knee injury, which was later diagnosed as a torn anterior cruciate ligament, which ended his 2020 season.

[107][108] During the game, Barkley rushed to the right and engaged with Bears safety Eddie Jackson, who wrestled him down to the ground near the sideline at the end of a six-yard run.

[111] On April 28, 2021, the Giants picked up the fifth-year option on Barkley's contract,[112] worth a guaranteed $7.217 million for the 2022 season.

[124] In the Wild Card Round of the playoffs, he had 109 scrimmage yards and two rushing touchdowns in the 31–24 victory over the Minnesota Vikings.

[139] Barkley had 17 carries for 147 yards and scored two touchdowns in the fourth quarter to lead the Eagles to a 15–12 win over the New Orleans Saints in Week 3.

[140] Barkley made his return to MetLife Stadium against the Giants in Week 7, rushing for 176 yards and a touchdown on 17 carries in a 28–3 victory over his former team.

[142] In Week 11 against the Washington Commanders, Barkley finished with 198 total yards and rushed for two touchdowns in the fourth quarter as the Eagles won 26–18.

[143] Barkley continued his dominance the following week against the Los Angeles Rams, recording 255 rushing yards and 302 total yards, highlighted by multiple 70-yard touchdowns in the second half as the Eagles won 37–20, netting him his fourth NFC Offensive Player of the Week title for the season.

However, due to the Eagles having already clinched the NFC East and the #2 seed in the playoffs, head coach Nick Sirianni announced that Barkley and other Eagles starters would rest for the season finale against the New York Giants, which precluded Barkley from possibly passing Dickerson's all-time record.

[150] Barkley finished the season leading the league with a franchise-record 2,283 yards from scrimmage, which was a league-high 34.8 percent of the team's output, while adding 15 touchdowns.

[151] He was named a First-team All-Pro, won the Offensive Player of the Year award, and finished third in MVP voting.

[152] In the Wild Card Round against the Green Bay Packers, Barkley rushed 25 times for a total of 119 yards to help the Eagles to a 22–10 win.

[154] Against the Commanders in the NFC Championship, Barkley ran for 118 yards and three touchdowns on 15 carries as the Eagles won 55–23, advancing to Super Bowl LIX.

He also set NFL records for most rushing (2,504) and scrimmage yards (2,857) in a full season, surpassing Terrell Davis.

[168] In 2018, the Pennsylvania General Assembly voted to make March 14 a state holiday known as "Saquon Barkley Day".