After only a handful of appearances with the Flyers and their American Hockey League (AHL) affiliate, the Adirondack Phantoms, Gostisbehere suffered an ACL tear that benched him for most of the 2014–15 season.

An acute injury to the knee in January 2020 forced Gostisbehere to undergo arthroscopy, and his performance continued to suffer when he was brought back prematurely from the surgery.

Gostisbehere underwent a second arthroscopic surgery during the NHL's COVID-19 shutdown and helped the Flyers advance over the Montreal Canadiens in the 2020 Stanley Cup playoffs.

He struggled to find a rhythm the following year, after missing the first six games of the season to COVID-19, and was further limited by a placement on waivers, another knee injury, and a two-game suspension that May.

[5] While skating with the Junior Panthers under-18 'AAA' ice hockey team, Gostisbehere helped to win the Presidents' Day AAA Challenge championship in 2007.

[9] On December 10, he scored his first collegiate goal as part of a 5–2 victory over Rensselaer Polytechnic Institute at the Festivus Faceoff in Lake Placid, New York.

[10] Gostisbehere earned ECAC Rookie of the Week honors at the start of February, when he matched a school record by scoring four assists in a 4–4 tie against Cornell.

[14] At the 2013 NCAA Division I men's ice hockey tournament, Gostisbehere scored one of Union's three power play goals in a 5–1 upset of reigning champions Boston College.

[15] Union's tournament run came to an end in the following game, when Matthew Peca scored a hat trick in the first three minutes and 12 seconds of the East Regional finals, buoying Quinnipiac to a 5–1 victory.

[17] In addition to scoring four goals and 13 assists in 22 ECAC games, Gostisbehere improved his defensive ability, finishing the regular season with a +18 plus-minus rating.

For his performance, Gostisbehere was named both the ECAC Hockey Co-Player of the Year, alongside St. Lawrence senior Greg Carey, and Best Defensive Defenseman.

[19] Gostisbehere additionally came in first in fan voting for the 2014 Hobey Baker Award, given to the top college hockey player in the US, and was named a top-10 finalist for the trophy.

In the championship game at Wells Fargo Center in Philadelphia, home of the team that drafted him, Gostisbehere scored one goal and two assists in a 7–4 victory over Minnesota.

Flyers general manager Ron Hextall intended for Gostisbehere’s call-up to be temporary as he searched for a veteran free agent to replace the injured skaters.

[27] On November 7, in his second game back in the AHL, Gostisbehere took a check from Kevin Raine of the Manchester Monarchs and felt a “pop” in his knee, later diagnosed as an anterior cruciate ligament injury.

[30] He impressed at training camp, scoring three goals in three preseason games, but an uneven defensive performance led head coach Dave Hakstol to send Gostisbehere to the Phantoms for the beginning of the 2015–16 season.

[32] He scored his first NHL point that same day, assisting in Wayne Simmonds’ game-tying goal in an ultimate 3–2 overtime win against the Carolina Hurricanes.

[36] On February 20, Gostisbehere became the first rookie in NHL history to score four overtime goals in one season when he helped defeat the Toronto Maple Leafs 5–4.

[38] Gostisbehere finished his rookie NHL season with 17 goals and 29 assists, and he became the youngest ever recipient of the Barry Ashbee Trophy, given to the Flyers' best defenseman.

[41] Following a disappointing postseason performance at the 2016 Stanley Cup playoffs, the Flyers revealed that Gostisbehere had played through the end of the season with a right hip injury.

[47] He began the 2017–18 season playing on the second defensive pair with Robert Hägg, only briefly teaming with Ivan Provorov on the top line.

[54] That offseason, Gostisbehere spent time at the Flyers' training facility in Voorhees Township, New Jersey, focusing on improving the mental aspect of his performance.

[58] Between Gostisbehere's injury and a series of healthy scratches, he appeared in only two of the Flyers' last 26 games before the COVID-19 pandemic forced the NHL to suspend play in March.

[64] After a slow start as he regained his offensive ability, Gostisbehere looked to be returning to form, scoring five goals in 10 games between late February and early March.

The suspension, the first of Gostisbehere's career, proved controversial, as the day before, Tom Wilson of the Washington Capitals had not been suspended for a high-profile hit on Artemi Panarin.

General manager Chuck Fletcher explained that Philadelphia had been hindered by the strict salary cap that the NHL had instituted for the 2021–22 season, and that the size of Gostisbehere's contract had made it difficult to retain him.

[70] Despite the team's poor record, Gostisbehere was happy with the trade, saying that coming to Arizona was "a little bit of a reset for my career" and "a good blend for myself and my family".

Early in his career, Gostisbehere chose to model his style of play after Panthers skater Pavel Bure, who was similarly undersized but used his speed to his advantage against larger players.

[81] As a rookie, most of Gostisbehere’s success came from his point production, but as his professional hockey career continued, he began to focus less on scoring and more on defense, particularly in power play scenarios.