The Killers are seen as one of the biggest rock bands of the 21st century, and the most successful to ever emerge from Nevada. They achieved worldwide success as a live band, performing in over 50 countries and on six continents, headlining venues such as Madison Square Garden and Wembley Stadium.

In 2001, Brandon Flowers was fired by his first band, a Las Vegas synthpop trio known as Blush Response. After attending an Oasis concert at the Hard Rock Hotel during The Tour of Brotherly Love, Flowers realized his calling was to be in a rock band and began searching for like-minded Musicians. He eventually came across an ad posted in a Las Vegas newspaper by Dave Keuning, a 25-year-old Guitarist who had moved to Vegas from Iowa a year earlier. When the pair met they bonded over similar musical influences and immediately began writing songs together in Keuning's apartment. In November 2001, they headed to Kill The Messenger Studio in Henderson, Nevada along with recently recruited Drummer Matt Norcross to begin recording a demo; they recorded two tracks: "Mr. Brightside", which was the first song Flowers and Keuning wrote together, and "Desperate". A month later they recorded two more, "Under the Gun" and "Replaceable", with Keuning's roommate Dell Neal on bass. "Mr. Brightside" has gone on to become a British cult-classic.

Ronnie Vannucci Jr. joined The Killers shortly before Neal's departure. Vannucci was well-known on the Las Vegas music scene, having played in numerous bands since he was young. It was while he was drumming for other bands including Daphne Major and Romance Fantasy in 2002 that he had met The Killers. Ronnie's first show with the band was on August 30, 2002, at a club called The Junkyard. Playing bass for The Killers that night was Mark Stoermer, who was at this point the lead Guitarist for local progressive rock band The Negative Ponies. The band were keen on Stoermer joining them on a permanent basis, but he was initially reluctant to commit. They had first approached him to be the second Guitarist when they were considering turning the band into a five-piece, "possibly more like the Strokes, with a keyboard". Stoermer mentioned later on that he could also play bass. The band had continued as a three-piece trying out other bassists until November 2002, when Stoermer eventually accepted the invitation to join. According to Ryan Pardey who booked many of the band's early shows "They (The Killers) became a great band when Ronnie and Mark joined. That’s when they finally became a cohesive unit. What Ronnie did — he was the discipline — and Mark was just a solid musician".

The band finished recording Hot Fuss in November 2003 with Jeff Saltzman, they decided to keep many of the previously recorded demos as they felt they had a spontaneity that re-recordings would not have. Shortly afterwards they returned to London having been invited to support British Sea Power on their UK tour, the band also worked with Alan Moulder at Eden Studios and Townhouse Studios mixing tracks for their upcoming album. They continued playing support slots during the first half of 2004 most notably touring both the US & UK with Stellastarr and opening for Morrissey on two separate occasions. The band filmed their first music video for the Spring 2004 release of "Somebody Told Me" which was to be the band's debut single in the US and second single in the UK. The band's first headline tour started in the UK in May 2004. During the spring and summer of 2004, the group played well-received sets at festivals across Europe and North America which helped add to their growing fanbase.

The Killers released their debut album Hot Fuss on June 7, 2004 in the United Kingdom on Lizard King Records and a week later in the United States on Island Records. The track listing differed depending on territory, in the UK and Australia "Glamorous Indie Rock and Roll" replaces "Change Your Mind" as track eight. Upon release Hot Fuss received generally favorable reviews from critics. Extensive touring and the success of the Grammy Award nominated singles "Somebody Told Me", "All These Things That I've Done" and "Mr. Brightside" led to the album becoming a huge commercial success. Hot Fuss reached number one in the UK in January 2005, seven months after its release, and has been certified 7x Platinum in both the UK and Ireland. It went on to spend more weeks on the UK Albums chart than any other that decade, 173 weeks in total. In the US the album reached its peak position of number seven in April 2005 and has been certified 3x Platinum It reached the top spot in Australia in March 2005, where it was certified 3x Platinum, it has also been certified 3x Platinum in Canada, Platinum in New Zealand and Gold in Argentina, Belgium, Germany and France. Mr. Brightside would eventually be downloaded 3.7 millions of times in the United States as of July 2017.

The Killers have won four NME Awards for "Best International Band" in 2005, 2008, 2009, and 2013. The band has won a BRIT Award for "Best International Band" in 2006 as well as a MTV Europe Music Award for "Best Rock Group" in 2006. Also in 2006, the band won for "Best Video" for "When You Were Young" at the Q Awards. To date, the band has received six nominations for "Best International Band" at the NME Awards, four nominations for "Best International Group" at the BRIT Awards, and three nominations for "Best Rock Group" at the MTV Europe Music Awards.

The Killers recorded a live session at Abbey Road Studios for Live from Abbey Road on November 29, 2006. They performed an almost totally unplugged set, which included stripped back versions of the album's title track "Sam's Town", "When You Were Young" and a rendition of the Dire Straits hit "Romeo and Juliet". In December 2006 the band released a Christmas charity song, "A Great Big Sled", which benefited Product Red. This has since become an annual tradition.

The band enlisted Stuart Price to produce their third studio album, he had previously remixed their songs under his Jacques Lu Cont moniker, the most notable being the remix of "Mr. Brightside". They first met Price at his London home in 2007 to discuss the possibility of him producing some unreleased tracks for their b-sides album Sawdust, however that same night they ended up in Price's home studio recording a demo of "Human" a new song that would become the eventual lead single from Day & Age. The band took six months apart following the completion of their Sam's Town tour, during this period they would send song ideas between each other and Price via Logic Pro. The band finished recording the album with Price at the band's newly acquired Battle Born Studios in Las Vegas.

Since 2008, The Killers have owned and operated Battle Born Studios (formerly Studio Vegas) in Winchester, Nevada.

The band embarked on the Day & Age World Tour, during which they performed on every continent except Antarctica and headlined US festivals Lollapalooza and Coachella for the first time. The tour was named one of the top fifty worldwide concert tours of 2009. On July 5–6, 2009 at the Royal Albert Hall, London The Killers recorded their first live DVD, "Live from the Royal Albert Hall". It was released in November and played at various cinemas across the globe. Live from Royal Albert Hall was certified 2x Platinum in the UK, Platinum in the US and Australia and Gold in Ireland and Brazil.

Invited by U.S. President Barack Obama, the band played on the White House South Lawn on July 4, 2010 for the second annual "Salute to the Military" United Service Organizations concert as part of Independence Day celebrations, which Flowers described as a "monumental honor". Despite their hiatus, the band got together to play "Human", "Somebody Told Me", "Mr. Brightside", "A Dustland Fairytale", "God Bless America/Read My Mind" and "When You Were Young". Flowers, Keuning and Stoermer also played at a campaign rally on July 8, 2010 in Nevada for Obama and U.S. Senate Majority Leader Harry Reid who was up for re-election. The Killers played an acoustic version of "Read My Mind" and did a folksy rendition of the state song, "Home Means Nevada". In February 2011, Flowers had a private lunch with Mitt Romney during Romney's visit to the Republican Party convention in Nevada. In 2012, the band remained neutral in the election. In 2015, Flowers performed a folksy rendition of the state song, "Home Means Nevada" for Obama and U.S. Senate Minority Leader Harry Reid at the National Clean Energy Summit. In 2017 the band wrote a letter opposing development on the Red Rock Canyon National Conservation Area.

Beginning in 2006, The Killers released annual Christmas themed singles and videos in aid of the charity Product Red, supporting The Global Fund to Fight AIDS, Tuberculosis and Malaria. The band released ten Christmas themed songs and music videos as singles: "A Great Big Sled" (2006), "Don't Shoot Me Santa" (2007), "Joseph, Better You than Me" (2008), "Happy Birthday Guadalupe!" (2009), "Boots" (2010), "The Cowboys' Christmas Ball" (2011), "I Feel It in My Bones" (2012), "Christmas In LA" (2013), "Joel the Lump of Coal" (2014), and "Dirt Sledding" (2015). On November 30, 2011 they released the (RED) Christmas EP on iTunes which features all six songs that had been released up to that point. Over the years they have enlisted the help of other Musicians and celebrities including Elton John, Neil Tennant (Pet Shop Boys), Toni Halliday (Curve), Wild Light, Mariachi El Bronx, Dawes, Owen Wilson, Jimmy Kimmel & Richard Dreyfuss. In 2016 they announced that they would be releasing no more Christmas singles but that they hoped another band would carry on the tradition, to wrap things up they released a compilation album Don't Waste Your Wishes featuring all ten previous singles plus a cover of the holiday classic "I'll Be Home For Christmas" which featured vocals from Brandon Flowers' former elementary school Teacher and Korean War veteran Ned Humphrey Hansen. All proceeds from the songs and the compilation album have been and will be donated to Product Red campaign and the fight against AIDS in Africa and as of 2016 they have raised over $1 million for the charity.

The Killers' fourth studio album Battle Born was released on September 18, 2012. The album became The Killers' fourth consecutive No. 1 album in the UK and Ireland and has been certified Platinum in the UK and Gold in Ireland, Mexico and Australia.

On September 11, 2013, the band tweeted a picture, which contained six lines of Morse code. The code was translated to "The Killers Shot at the Night". On September 16, 2013, exactly ten years to the day of their first show in London, The Killers released "Shot at the Night" which was produced by Anthony Gonzalez. It was also revealed that they would be releasing their first greatest hits compilation, Direct Hits released on November 11, 2013, celebrating a decade together as a band and fulfilling a contractual requirement with their record label. The album featured songs from all four studio albums, the new single "Shot at the Night" and another new song "Just Another Girl".

The release of Direct Hits was followed by a short promotional tour, the band also played a number of festivals in 2014.

The band headlined the opening night of the new T-Mobile Arena on the Las Vegas strip on April 6, 2016, the band were joined during their set by a number of guests including "Mr. Las Vegas" Wayne Newton and The Blue Man Group On May 24, 2016, the band announced that Mark Stoermer was taking a break from touring "to pursue other educational goals and releasing a solo album". The statement emphasized that Stoermer was still involved in working on the band's fifth album and will still occasionally perform live with them in the Future. In Stoermer's absence touring keyboardist/guitarist Jake Blanton moved to bass guitar. On September 30 and October 1, 2016, the band (including Stoermer) celebrated the tenth anniversary of their second album, Sam's Town, by playing two nights at the Sam's Town Hotel and Gambling Hall, which the album was named after. For these shows, they played the album in full from start to finish. The band contributed a track titled "Mixed Signals" to Robbie Williams' eleventh studio album, The Heavy Entertainment Show, released in November 2016.

The Killers song "Goodnight, Travel Well" was used in an effort to promote awareness for sex trafficking headed by UNICEF, MTV EXIT: End Exploitation And Trafficking and the US Agency for International Development. "Hotel California" was covered by The Killers and Rhythms del Mundo with proceeds benefiting climate crisis and natural disaster relief. The song "Ultraviolet (Light My Way)" was covered by The Killers with proceeds benefiting famine-stricken areas. The band headlined the 2017 Global Citizen Festival.