Selected by the Edmonton Oilers in the first round (No. 22) of the 2008 NHL Draft, Eberle scored shorthanded in his NHL debut against the Calgary Flames on Oct. 7, 2010. He led the Oilers during his rookie season with 43 points (18 goals, 25 assists) in 69 games and was named to the 2011 NHL All-Star Game.

Eberle broke out in his second NHL season (2011-12); he was named to the NHL All-Star Game and had NHL career highs with 34 goals and 76 points in 78 games. He had 10 minutes in penalties and finished second to Brian Campbell of the Florida Panthers in voting for the Lady Byng Trophy, awarded to the player judged to best combine sportsmanship and gentlemanly play and a high standard of play.

Eberle scored the final hat trick at Rexall Place against the Toronto Maple Leafs on Feb. 11, 2016. He was a five-time 20-goal scorer for the Oilers before they traded him to the Islanders on June 22, 2017.

He scored 25 goals in his first season with New York (2017-18), then played a key role in New York's sweep of the Pittsburgh Penguins in the 2019 Eastern Conference First Round, scoring in each game. Eberle finished the postseason with nine points (four goals, five assists) in eight games. He signed a five-year contract with the Islanders on June 14, 2019.

Eberle was selected by the Seattle Kraken at the 2021 NHL Expansion Draft and was named an alternate to captain Mark Giordano. He scored the first hat trick in Kraken history in a 5-2 win against the Buffalo Sabres at the Climate Pledge Arena on Nov. 4, 2021, becoming the ninth NHL player to score a natural hat trick for an expansion team in its inaugural season. Eberle also scored the first Stanley Cup Playoff overtime goal for Seattle, a 3-2 win against the Colorado Avalanche in Game 4 of the 2023 Western Conference First Round.

Eberle signed a two-year, $9.5 million contract with the Kraken on March 8, 2024. He was plus-1 in 19:24 of his 1,000th NHL game, Seattle's 5-4 overtime loss to the Vegas Golden Knights three days later. On Oct. 8 of that year, he was named the second captain in Kraken history, replacing Mark Giordano. He then signed a two-year, $11 million contract (average annual value of $5.5 million) to stay in Seattle on March 6, 2026.

On the international stage, Eberle helped Canada with the 2009 IIHF World Junior Championship. In 2010, he was named tournament MVP and best forward at the World Junior Championship, when Canada finished second.