Guthrie first made a name for himself by releasing a series of self-produced cassettes, and subsequently released albums on Three Gut Records. He was nominated for a Juno Award for 2003 album Now, More Than Ever. In June 2013, his solo studio album Takes Time was longlisted for the 2013 Polaris Music Prize. The name of the album is a nod to the delay of the album's completion and release, which he began recording in 2007. He performed at NPR Music as part of their Tiny Desk Concerts series in support of the album's release. 
Jim Guthrie Vs. The Haymakers was a limited release split EP released in 2003, featuring four songs by each artist. Jim Guthrie contributed four instrumentals, created using the Sony PlayStation MTV Music Generator, while Haymakers contributed three songs which would eventually be released on their album II, and one song ("Gravy") which was exclusive to the Jim Guthrie Vs. The Haymakers release.
His song “Who Needs What”, from the 1999 album A Thousand Songs, was covered by the indie pop band Tullycraft on their 2002 album Beat, Surf, Fun.
Since the 1990s he has collaborated with Guelph-based hip-hop artist Noah23 on numerous projects, including an appearance on his 2008 album Rock Paper Scissors.