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On July 22, 2020, the NLL awarded an expansion franchise to the city of Fort Worth and owner Bill Cameron. It was announced that the team would begin play in the 2021–2022 season, with its home arena being Dickies Arena.

At a press conference on November 17, 2020, the franchise officially became the Panther City Lacrosse Club. The team's unique name is in reference to Fort Worth's "Panther City" nickname, which stems from an 1875 article in the Dallas Herald that derisively characterized the city's economy as being so slow that a panther could sleep in the street by the courthouse. Although an intended insult, the name Panther City was enthusiastically embraced by locals after Fort Worth recovered economically. The team is also the league's first member to use the "Lacrosse Club" moniker, similar to teams in the Premier Lacrosse League.

On January 25, 2021, former Philadelphia Wings assistant Tracey Kelusky was named the team's first head coach.

Inaugural season

Panther City debuted on December 4, 2021, against the Wings in Philadelphia. Travis Cornwall scored the first goal in franchise history as Panther City took a 1–0 lead. Despite leading 7–4 at halftime, the team could not start 1–0 as they fell to the Wings, 12–11 in overtime. A week later on December 10, the franchise played its first ever home game at Dickies Arena, where they fell to the Vancouver Warriors, 14–8 in front of 7,309 fans. After five games, Panther City got their first franchise win on January 15, 2022, on Long Island against the New York Riptide, 13–12 thanks to an overtime goal from rookie forward Patrick Dodds. It took a month and a half and four more tries, but Panther City notched their second win and first ever home win on February 26, 11–10, in a rematch with the Warriors in front of 4,714 fans. Again it would be Patrick Dodds providing late-game heroics with a goal with 39 seconds remaining. The next week, Panther City collected a consecutive win for the first time, and set a franchise record for goals scored with a 17–16 home overtime win over the Saskatchewan Rush.

The streak would eventually climb to five games, catapulting the team back to the playoff race with a 6–8 record. Panther City would hang in there until the penultimate week of the regular season when they lost to the Georgia Swarm. A home loss to Saskatchewan closed out the year, though Panther City still posted the best inaugural season record by an expansion team since the San Diego Seals in 2018–19.