Nighbor played his early hockey in his hometown of Pembroke with the Pembroke Debators in 1910-11. From here he moved onto the Port Arthur Bearcats in 1911-12, and then to the Toronto Blueshirts of the NHA, in 1912-13. In his first professional season with the Blueshirts he bagged 25 goals, 0 assists for 25 points in 19 games.

The 1913-14 season saw Frank jump to the Vancouver Millionaires of the PCHA where he played for two seasons, and was voted to the PCHA First All Star Team in 1915. Here, with team mates Cyclone Taylor and Mickey MacKay, Nighbor led Vancouver to the Stanley Cup, defeating his future team, the Ottawa Senators. In the two seasons he was with Vancouver, Frank managed to score 33 goals, 12 assists for 45 points in 28 games, well over a point a game.

In the early days of hockey players were paid hefty sums of money to move from league to league. It was not uncommon for players to play in several different leagues over their careers, each time, making more money. Frank Nighbor was no different, so in 1915-16 he jumped to the NHA's Ottawa Senators. It should be noted here that the Ottawa Senators had 2 teams in the NHL. The first played from 1917 to 1934 and the second team began in 1992.

While in his final season in the NHA, Frank tied Joe Malone with 41 goals to lead the league in goals. The Ottawa Senators moved to the NHL when it was formed in 1917. Frank wasted little time in establishing himself as a scoring threat in the new NHL in its inaugural season of 1917-18. In 10 games he scored 11 goals and 8 assists. Frank's production increased over the next two seasons. In 1919-20 Nighbor had 26 goals, 15 assists in 23 games and also led the league in Playoff scoring and points with 6 goals, 1 assist for 7 points. In that same year, Ottawa won it's first ever Stanley Cup, defeating the Seattle Metropolitans. Although the 1919-20 season was Frank's pinnacle season in terms of point production, it didn't stop him from continuing to be a dominating force in the new NHL. He continued to be in the top 10 scoring list until the end of the 1920-21 season, and then later reappeared on the list in 1925-26.

It has been recorded that Frank possessed a skating ability rivaled by few players of his era. His playmaking prowess and great defensive ability made him a threat no matter where he was on the ice. Before the NHL was formed, Nighbor had twice scored 6 goals in a game, a number which by today's standards would rank him second in most goals in a game, and he would be only the second player in any era to have done it twice, Joe Malone had a 7 and a 6 goal game in his career.

Frank was the first recipient of the Lady Byng Trophy in 1925, and a year later he became the first winner of the Hart Trophy. On January 31, 1930, Frank was traded to Toronto for Danny Cox and cash. In his final NHL season, Nighbor socred only 2 goals in 41 games. Frank played 1 game for the Buffalo Bisons of the IAHL in 1930-31 and then moved to a coaching career with the Bisons for the following two seasons. King Clancy said of Nighbor, "Nobody could handle a hockey stick like Frank Nighbor." One of the NHL's true all time greats, Frank was named to the Hockey Hall of Fame in 1947.