He serves as the co-founder, lead vocalist, primary songwriter, keyboardist, and occasional bassist of the Las Vegas-based rock band the Killers, which he formed with Dave Keuning in 2001.

In addition to his work with the Killers, Flowers has released two solo albums, Flamingo (2010) and The Desired Effect (2015).

[14] His parents met as teenagers, and he wrote the song "A Dustland Fairytale" as a tribute to their marriage and lifelong romance.

[15] His grandmother was from Lithuania,[16] and his cousin is Craig Barlow, an inductee to the Las Vegas Golf Hall of Fame.

"[21] Flowers responded to an ad that Dave Keuning had placed in the Las Vegas Weekly in late 2001, whereupon they became the Killers.

Flowers wrote the lyrics to the single "All These Things That I've Done" that numbered among the "100 Greatest Songs of All Time" by The Daily Telegraph and earned one of the band's seven Grammy nominations.

It became Flowers' first top ten single in the UK as a solo artist and was certified silver by the BPI.

[36] After some of the band members wanted "to take a break from touring and the rat race," Flowers decided to keep it going and record a second solo album.

[39][40] The album featured performances by artists including Bruce Hornsby, Tony Levin (Peter Gabriel), Joey Waronker (Beck), Carlos Alomar (David Bowie), and Kenny Aronoff (John Mellencamp).

[46][47][48][49] The album was preceded by positively reviewed singles "Can't Deny My Love", "Still Want You", "Lonely Town", and "I Can Change".

[60][61] Flowers was one of two favorite artists asked to perform "Be Still" and "Home Means Nevada" at the funeral of former U.S. Senate Majority Leader Harry Reid on January 8, 2022.

[63] In addition to his work with the Killers, Flowers has collaborated with Alex Cameron,[64] Avicii,[65] New Order,[66] and Robbie Williams.

[67] In 2023, he performed alongside Elton John at the Glastonbury Festival wearing a red suit, black shoes with a pale blue shirt.

[68] Flowers married Tana Mundkowsky in 2005 and lives in Las Vegas, Nevada, and Park City, Utah.

[83][84] The Killers co-organized a benefit concert in December 2017 for those affected by the 2017 Las Vegas shooting, raising more than $700,000.