He was named as an All-Australian at the 2007 NAB AFL U18 Championships. He was drafted by Melbourne in the 2007 National Draft at pick 14, but was placed on the long term injury list due to stress-related back problems. He made his debut in the final game of the 2008 AFL season but suffered a further back injury in the early part of the 2009 season.
Jack Grimes suffered a season-ending injury in the round 7 match against the Adelaide Crows.
On 3 February 2012 he was named, alongside fellow youngster Jack Trengove as the co-captain of Melbourne Football Club. At 22 years of age he was one of the youngest ever captains in VFL/AFL history. In 2014, Grimes continued on as co-captain, this time with Nathan Jones. However, on 1 December 2014 it was announced that he had stepped down as the club's co-captain.