Sewell was selected by the Hawthorn Football Club with the 7th overall pick in the 2003 Rookie Draft. 2006 proved to be his breakout year, when he was third in the club's Best and Fairest, collecting 130 votes behind Sam Mitchell and Luke Hodge. He played all 22 games for the season, and kicked his first and second goal in the last match of the year against Geelong. In 2007, Sewell was a key player for Hawthorn as he went to win the Peter Crimmins Medal, winning by one vote over runner-up Campbell Brown. On 27 September2008, Sewell became a Premiership player, after the Hawks beat the reigning premiers Geelong in the Grand Final. Sewell was outstanding on this day coming 3rd overall in the Norm Smith medal voting. In the final round of 2009, Sewell suffered a fractured cheekbone and eye socket when he was knocked out by a shirtfront from Essendon captain Matthew Lloyd early in the third quarter. This was the turning point in the match, as Hawthorn went on to lose the match and miss the finals after leading at the time of the incident. Lloyd later received a 6-week suspension for the hit; a month after the incident, Lloyd announced his retirement. In September 2013, Sewell became a dual Premiership player when the Hawks defeated the Fremantle Football Club in the 2013 AFL Grand Final. 2014 was his final season, Sewell twice suffered from hamstring injuries. The first in the final practice match before the season began and then again in round 16, early in a game against. He managed ten games for the season with his last game being the Second Qualifying Final against.
Sewell's brother, Myles, won the J. J. Liston Trophy for North Ballarat in 2009. He also has two other siblings: brothers Adam, and sister Mikaela. In 2011, Sewell completed a Bachelor of Commerce with a Sport Management Degree from Deakin University. In 2017, Sewell graduated from Monash University with a Master's in Business Administration. In March 2016, Sewell, along with ex-teammate Michael Osborne, launched the Australian Rules Football College. Based in North Melbourne, and based on a US college model, the Australian Rules Football College focuses on developing the football skills of their students, whilst also placing an emphasis on education, through offering certificates in health, personal training, massage, leadership, management and diplomas in business. Sewell is currently a commentator for Network 7, and occasionally plays for Newlyn in the Central Highlands Football League.