Barkley had 27 carries for 159 yards and a touchdown. He also had three receptions for 40 yards and a TD.
The Eagles (6-2) held on after coach Nick Sirianni wasted chances to put easy points on the board. The Eagles went 0 for 2 on fourth down and were 0 for 3 on 2-point conversions, forcing them to let Jake Elliott try a 57-yard field goal with 2:16 left.
Elliott missed, giving the Jaguars (2-7) the ball at their own 47-yard line.
Eagles defensive back Avonte Maddox was flagged 18 yards for pass interference that helped move the ball to the Eagles 13.
But Jacksonville's second-half rally ended when Trevor Lawrence's terrible pass was picked off in the end zone by Dean for the linebacker's first career interception.
The Eagles have found their groove out of the bye, riding a winning streak behind Jalen Hurts and Barkley that has thrust them into the thick of the NFC East race.
Hurts was 18 of 24 for 230 yards. He threw for two scores and ran for another.
DeVonta Smith nearly matched Barkley with a play straight out of a video game on a one-handed 25-yard TD grab - reminiscent of New York Jets receiver Garrett Wilson's catch last week - late in the fourth that stretched the Eagles' lead to 28-16.
But all those lost points haunted the Eagles.
Lawrence - 16 of 31 for 169 yards and two interceptions - ran for two touchdowns for the Jaguars, including a 4-yard scramble with 4:04 left that made it 28-23.
The Eagles can credit Barkley for this win.
Barkley, already proving a pivotal free agent pickup for the Eagles, starred in another dominant effort with arguably the most acrobatic play of the NFL season.
The play that left mouths agape: Hurts dumped a pass to Barkley in the second quarter and he faked out one defender and used a filthy spin move that left another Jaguars defender flailing on the ground before he pulled off a split-leg, backward leap over Jacksonville cornerback Jarrian Jones for the 14-yard gain.
The reverse hurdle stunned the Jaguars and set up an Eagles field goal for 10-0 lead. But Barkley also had a costly mistake.
Lawrence ignited Jacksonville's second-half rally when he scored on a 1-yard run and threw a 2-point conversion pass late in the third to make it 22-8. Barkley then fumbled on the next possession, the loose ball scooped by Travon Walker and returned 35 yards for a TD. The Jaguars cut it to 22-16 after another 2-point conversion.
The Eagles, wearing their fan-favorite, throwback Kelly green uniforms, let Barkley handle the bulk of the offense in the first half.
Barkley sure didn't settle for the routine plays for much of the game. Before he hurdled for a first down, Barkley hauled in an over-the-shoulder 20-yard touchdown catch in the corner of the end zone to make it 7-0 - significant for the lead, yes, but also the Eagles scored their first points in the first quarter all season.
After an Eagles touchdown was wiped out on offensive pass interference, Barkley got the ball on the next play and hustled 19 yards for the score and a 16-0 halftime lead.
Unhappy homecoming
Jaguars coach Doug Pederson fell to 0-2 against the Eagles since Philadelphia fired him after the 2020 season.
Injuries
Jaguars: OL Mitch More was treated for a concussion. ... OL Anton Harrison suffered a knee injury. ... OL Cooper Hodges was carted off the field with a leg injury in the third quarter.
Eagles: WR A.J. Brown suffered a knee injury. ... LB Ben VanSumeren also suffered a concussion.
Eagles lose star receiver A.J. Brown against Jacksonville to knee injury
Eagles wide receiver A.J. Brown left Sunday's game against Jacksonville with a knee injury.
Brown was slow to get up following his final catch of the game late in the first half. He had two catches for 36 yards before he was ruled out in the second half.
Brown already missed three games this season with a hamstring injury. He has two 100-yard receiving games this season and entered Sunday with 21 catches for 408 yards and three touchdowns.
Brown had 106 catches for 1,456 yards and seven touchdowns last season for the Eagles and has been one of the top receivers in the NFL since his rookie season with Tennessee in 2019. Brown signed a three-year contract extension in April that included $84 million in guaranteed money.
Up next
Jaguars: Return home Sunday to play Minnesota.
Eagles: Travel for Sunday's game at Dallas.