The band was formed by guitarist/vocalist Dave Mustaine and bass guitarist David Ellefson in the year 1983. Despite many line-up changes, Megadeth is partly responsible for the popularization of thrash metal in the late 1980s. The band was also notorious for its substance abuse, a contributing factor to their continuous revolving door of band members. The group nonetheless found sobriety and a stable line-up with 1990 release Rust In Peace, a trend which continued until 1998 with the departure of drummer Nick Menza. During that period, the band released four studio albums, including Countdown To Extinction, which is Megadeth's most commercially successful album.

Dave Mustaine disbanded Megadeth in 2002 due to a nerve injury he had suffered on his left arm. Following a year of physical therapy Mustaine began work on what was to be his first solo album, however contractual obligations forced The System Has Failed to be released under the Megadeth name, following which, Mustaine decided to reform the band in 2004. The band has since released five studio albums, but continued to have several line-up changes through 2000s and 2010s, with Mustaine remaining the only constant member. Co-founder Ellefson, who took legal actions against the band during the disbandment, rejoined in 2010 but was fired from the band in 2021.

Winner of one Grammy Award:
- Best Metal Performance for "Dystopia" from Dystopia album.

2023-present
Dave Mustaine - lead vocals, guitars
Teemu Mäntysaari - guitars
James LoMenzo - bass
Dirk Verbeuren - drums

2021-2023
Dave Mustaine - lead vocals, guitars
Kiko Loureiro - guitars
James LoMenzo - bass
Dirk Verbeuren - drums

2016-2021
Dave Mustaine - lead vocals, guitars
Kiko Loureiro - guitars
David Ellefson - bass
Dirk Verbeuren - drums

2015-2016
Dave Mustaine - lead vocals, guitars
Kiko Loureiro - guitars
David Ellefson - bass
Chris Adler - drums

2010-2014
Dave Mustaine - lead vocals, guitars
Chris Broderick - guitars
David Ellefson - bass
Shawn Drover - drums

2008-2010
Dave Mustaine - lead vocals, guitars
Chris Broderick - guitars
James LoMenzo - bass
Shawn Drover - drums

2006-2007
Dave Mustaine - lead vocals, guitars
Glen Drover - guitars
James LoMenzo - bass
Shawn Drover - drums

2004-2006
Dave Mustaine - lead vocals, guitars
Glen Drover - guitars
James McDonough - bass
Shawn Drover - drums

2000-2002
Dave Mustaine - lead vocals, guitars
Al Pitrelli - guitars
David Ellefson - bass
Jimmy DeGrasso - drums

1998-2000
Dave Mustaine - lead vocals, guitars
Marty Friedman - guitars
David Ellefson - bass
Jimmy DeGrasso - drums

1989-1998
Dave Mustaine - lead vocals, guitars
Marty Friedman - guitars
David Ellefson - bass
Nick Menza - drums

1987-1989
Dave Mustaine - lead vocals, guitars
Jeff Young - guitars
David Ellefson - bass
Chuck Behler - drums

1983-1987
Dave Mustaine - lead vocals, guitars
Chris Poland - guitars (1984-87)
David Ellefson - bass
Gar Samuelson - drums (1984-87)