Loomis got his first instrument at nine or ten years old, but didn't start practicing seriously until around the age of 15. As a teenager in Wisconsin he played in a handful of cover bands and three death metal bands before joining more established bands. At the age of 16, Loomis won Wisconsin's Guitar Wars contest.
He was auditioned for Megadeth (during the So Far, So Good...So What! era) at the age of 16, after their lead guitarist Jeff Young was fired from the band. After they played a few songs together, Dave Mustaine, the band's frontman and other lead guitarist, thanked Loomis and told him that one day he would become a great guitar player, but because of his age he was not right for the position. Jeff Loomis saw Cacophony on tour, and told Marty Friedman, who became very interested, about the audition. Marty tried out for the position and joined the band in 1989. In 2005, Loomis would then share the stage with Megadeth, as the lead guitarist for Nevermore as part of Mustaine's Gigantour festival. Jeff began to work on his solo album "Zero Order Phase". At this time Megadeth were having tryouts for a new guitarist once again and invited Jeff to join them. Jeff turned the band down in order to keep working on his solo album. Coincidentally, Loomis' co-guitarist in Nevermore, Chris Broderick, auditioned for Megadeth and was given the part.
Not too long after being auditioned for the lead part in Megadeth (which was also auditioned for by Steve Smyth and Chris Broderick, both playing for his later band Nevermore at different points), Loomis was unable to join the band Sanctuary after guitarist Sean Blosl had left. He was able to take his place at this time; however, because of a dispute caused by guitarist Lenny Rutledge wanting to make grunge oriented music, Sanctuary broke up 4 months afterwards.
After the break-up, Loomis and former Sanctuary members Warrel Dane (vocalist) and Jim Sheppard (bassist) made plans to form Nevermore, and in late 1994, Loomis became the lead guitarist of Nevermore after the brief period being in Sanctuary. During his time in the band he was the main songwriter of Nevermore, adding to the unique sound that fans are familiar with. His contributions can be found in albums such as The Politics of Ecstasy, Dreaming Neon Black, This Godless Endeavor (including Steve Smyth, who previously featured in the band Testament) and Nevermore's 2010 album, The Obsidian Conspiracy. Loomis played an important role in portraying the sound that Nevermore has today, using 7 string guitars and techniques such as sweep-picking. One of his more important musical showcases is in the critically acclaimed album Dead Heart in a Dead World, in which he wrote most of the songs before Nevermore. On the 21st of April 2011, he along with Van Williams left Nevermore citing personal and musical differences with Warrel Dane.
In 2005, Jeff reported that he would take some time as a break and then begin recording a solo album. He said, "It's something I've been wanting to do for sometime... It will be like a Jason Becker/Marty Friedman kind of thing." On April 1, 2008, Jeff said that all 10 songs which have been written have had the drumming recorded (which was done by Mark Arrington pretty much overnight) and they will soon begin tracking the rhythm guitar. On 3 July 2008, it was announced that the album would be called Zero Order Phase . It was released 30 September via Century Media Records. During this time Dave Mustaine of Megadeth invited Jeff to join as the lead guitarist, but he declined the offer to work on his solo record. In an interview to Guitar Asylum, Jeff confirmed that a new solo record is in the works, and spoke about the possibility of having guest work by Chris Poland and Rusty Cooley. It is confirmed that guest solos on a second solo album will be done by Marty Friedman, Tony MacAlpine and Chris Poland.
It was announced on January 30, 2012, in a press release that included track listing and cover art, that the name of the new album will be Plains of Oblivion slated for release April 10, 2012 through Century Media Records