Selected by the Buffalo Sabres in the first round (No. 26) of the 2008 NHL Draft, Ennis got started quickly in the NHL by scoring 20 goals in 2010-11, his first full season.

Ennis had shown his scoring touch early on with consecutive 43-goal seasons for Medicine Hat of the Western Hockey League in 2007-08 and 2008-09. He led Medicine Hat in all major scoring categories in 2007-08 and skated in the Canadian Hockey League Top Prospects Game. Ennis was an alternate captain for Team WHL during the 2008 Canada-Russia Challenge, was named the league's Most Sportsmanlike Player and selected to the WHL East Division First All-Star Team.

In 2008-09, Ennis led Medicine Hat with 85 points during the regular season and 19 points in the playoffs. He was again selected to WHL East Division First All-Star Team and named Most Sportsmanlike Player for the second straight season. Selected to Canada for the 2009 World Junior Championship, Ennis had three goals and seven points to help his country finish first.

With Portland in 2009-10, Ennis had 23 goals and 65 points and was named American Hockey League Rookie of the Year. Ennis got his first AHL goal, assist and hat trick in a four-point performance against Hartford on Oct. 16, 2009. He was named MVP of the 2010 AHL All-Star Game after scoring three points.

Ennis scored a goal in his NHL debut against the Philadelphia Flyers Nov. 27, 2009 and played 10 games for Buffalo that season. He made his Stanley Cup Playoff debut April 15, 2010, against the Boston Bruins and got an assist for his first NHL playoff point two days later. His first Stanley Cup Playoff goal came April 23, 2010, also against the Bruins.

Appearing in all 82 games in 2010-11, Ennis had 20 goals and 49 points, ranking fourth in NHL rookie scoring. He was the first Sabres rookie to score 20 goals since Thomas Vanek (25) in 2005-06 and had the most points by a Sabres rookie since Derek Plante had 56 in 1993-94. The Sabres were 14-2-2 when Ennis scored a goal, and 12-1-1 in his multipoint games.

Ennis led the Sabres at plus-11 in 2011-12, when Buffalo went 27-13-8 with him in the lineup; he missed 34 games because of injury. The Sabres were 15-3-5 when he had a point and 7-1-1 when he had more than one point. In 2012-13, he shared the team lead in assists with 21.

The following season, Ennis led the Sabres with 21 goals and had a six-game point streak from Jan. 12-23, 2014. In 2014-15, he had three points in a game four times.

After eight seasons with the Sabres, Ennis was traded to the Minnesota Wild on June 30, 2017. He played one season in Minnesota as a depth forward, was bought out from the final season of his initial five-year contract and signed a one-year contract with the Toronto Maple Leafs on July 6, 2018. He had his first NHL hat trick for Toronto in a 6-2 win against the Calgary Flames on March 4, 2019.

Ennis was on the move again when he signed a one-year contract with the Ottawa Senators on July 1, 2019. He had 33 points (14 goals, 19 points) in 61 games when he was traded to the Edmonton Oilers on Feb. 24, 2020.