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The band completed recording Eyes Open in December 2005, with Jacknife Lee returning for production, and this album was released in the UK on May 1, 2006, with the first UK single "You're All I Have" having been released on April 24, 2006. The album was released in North America on May 9. While "Hands Open" was the first American single, "Chasing Cars" pushed its way onto the download and pop charts after it was heard in the second season finale of the television show Grey's Anatomy on May 15, 2006. Due to the song's surprise popularity, it was released as an overlapping single in early June and the video was re-recorded to include clips from the show. Also, it was featured in another television show "One Tree Hill" during its season finale. Another of their songs, "Open Your Eyes", was heard on the season finale of another medical program, ER, on May 18, 2006, the The 4400, and the season premiere of Grey's Anatomy on September 28, 2006.

The band was forced to postpone a majority of the American Eyes Open tour after polyps were discovered on Lightbody's vocal cords, and failed to heal after initial postponement of three dates on the tour. Dates were rescheduled for September. The year would continue to be difficult on the band for the U.S. legs of their tours, as they were also forced to cancel two west coast festival appearances in mid-August due to the threat of terrorist attacks on U.S.-bound flights from the UK. Two band members made it to the U.S. while two were stuck in London. Sequentially, they all made it to the lone U.S. tour stop in Boston days later but failed to recover any of their luggage, forcing them to shop for clothes on Newbury St. that afternoon. Their gear arrived hours before showtime, just in time for sound check.

Earlier on in the year at the Pukkelpop festival in Hasselt/Kewit Belgium, in which security problems regarding the bands equipment at Heathrow airport meant they lost all their instruments in customs, but managed to bring two of their acoustic guitars with them. This saw two members of the band perform a short acoustic set, with Gary Lightbody saying Next time we'll bring our equipment on the plane, even if it kills us!.

The band also had to cancel appearances in Germany and France after bassist Paul Wilson injured his left arm and shoulder.

Eyes Open on the 26th November 2006 became the UK's best-selling album of the year so far shifting 1.2 million copies.