Known for their technically complex guitar work and musicianship, Megadeth is one of the "big four" of American thrash metal along with Metallica, Anthrax, and Slayer, responsible for the genre's development and popularization. Their music features complex arrangements and fast rhythm sections, dual lead guitars, and lyrical themes of war, politics, religion, death, and personal relationships.

In 1985, Megadeth released their debut album, Killing Is My Business... and Business Is Good!, on the independent record label Combat Records, to moderate success. It caught the attention of bigger labels, which led to Megadeth signing with Capitol Records. Their first major-label album, Peace Sells... but Who's Buying?, was released in 1986 and was a major hit with the underground metal scene. Band members' substance abuse issues and personal disputes had brought Megadeth negative publicity during the late 1980s. Nonetheless, the band went on to release a number of platinum-selling albums, including So Far, So Good... So What! (1988), Rust in Peace (1990), and Countdown to Extinction (1992). These albums, along with worldwide tours, brought them public recognition.

Megadeth has had numerous guitarists, drummers and bassists throughout its 40-year career, with Mustaine being the only remaining original member of the group. The band temporarily disbanded in 2002 when Mustaine suffered an arm injury and re-established in 2004 without longtime bassist David Ellefson, who had taken legal action against him. Ellefson settled out of court and rejoined the band in 2010, but was fired in 2021 amid allegations of sexual misconduct. Megadeth's current lineup includes Mustaine, bassist James LoMenzo, guitarist Kiko Loureiro and drummer Dirk Verbeuren.

Megadeth earned platinum certifications in the United States for five of its sixteen studio albums, and has received twelve Grammy nominations. Megadeth won its first Grammy Award in 2017 for the song "Dystopia" in the Best Metal Performance category. The band's mascot, Vic Rattlehead, regularly appears on album artwork and live shows.