The official video begins with words being typed on the screen stating "A global virus of catastrophic proportions has attacked the entire male population. Only two male models from Colorado survive... this is their story". The screen shifts to a shot of the band in briefs at a photo shoot. The set resembles that of a hotel. Another photo shoot takes place at a set resembling a high school wrestling match, where they are dressed in neon-colored singlets. The last photo shoot is in the prehistoric era, and the band is dressed as cavemen. The video ends with a shot of a mushroom cloud, and the words "Transmission terminated" are typed onto the screen. The video received a nomination at the 2009 MTV Video Music Awards for Best New Artist.
"Don't Trust Me" became the band's breakout hit. It is their first top 10 hit in the U.S, reaching #7 on the BillboardHot 100 in its 23rd week on the chart. It has also been a huge success on U.S. Mainstream Top 40 radio, reaching #1 there. It has gone top 40 on the Canadian Hot 100 as well, at #6. "Don't Trust Me" has done particularly well in Oceania, where it has reached the top 3 in Australia, and the top 10 in New Zealand. It has also reached #5 in Finland. On July 19, 2009, the single entered the UK singles charts at #21. On April 26, 2010 "Don't Trust Me" re-entered the UK top 40 at #22.
As of June 2013, the single has sold 3,322,000 digital units in the United States.