This song samples Janko Nilovic's "In The Space" from his 1970 album Psyc Impressions.

Jay-Z explained to Funkmaster Flex and Mister Cee at New York City's Hot 97 radio station that in this song, he's taking aim at artists who use Auto-Tune as a crutch. He went on to elaborate about who he was not getting at. Said the Brooklyn MC: "The guys who did it, did it great. T-Pain, he does great melodies. If you listen to Kanye, great melodies. If you listen to [West's] 'Say You Will' or 'Heartless,' great melodies. [Lil Wayne and T-Pain's] 'Lollipop' was a fantastic melody. Everybody can't do it. Let them guys do it. They got their little niche, let's move on. That's just my opinion. I don't know if everybody feels the same way." Jay-Z concluded that his intention with the record was to "draw [a] line in the sand."

Jay-Z explained to the Chicago radio station WGCI that hearing the use of Auto-Tune in an advert for Wendy's fast-food chain, was one of the inspirations for this song. He said: "I just think in hip-hop, when a trend becomes a gimmick, it's time to move on. I saw a Wendy's commercial and they're using Auto-Tune. They're joking on it. It's like, OK, enough of that... It was a trend, it was cool in the beginning. Some people made great music with it, now it's time to move on."

Kanye West co-produced this track and also contributed vocals to the bridge. Though West served as the co-producer of The Blueprint³, it was surprising that he was involved on this track because of his heavy use of auto-tune on his 808's and Heartbreak album. West told MTV News: "We actually removed all the songs with Auto-Tune off of his album, to make the point that this is an anti-Auto-Tune album, even though I released an album that has all Auto-Tune!"

The bridge samples Steam's 1969 chart-topper, "Na Na Hey Hey Kiss Him Goodbye." Two other 2009 songs utilized the same song. Washington DC rapper Wale riffed on the track on his single "Chillin'" and Kristinia DeBarge also borrowed from it for her debut number "Goodbye."

The song's music video was inspired by the anti-establishment 1970 film, Zabriskie Point, which was about young American hippies. Jay-Z explained to MTV News: "The visual for 'D.O.A.' conveys the direction for Blueprint 3 and is inspired, in part, by the film Zabriskie Point, directed by Michelangelo Antonioni. The film parallels the vision of Blueprint 3. Zabriskie Point represents aspects of a counterculture movement. In music, we have to elevate beyond what has become a popular trend or gimmick, pushing ourselves past what is comfortable and challenge the status quo."

Jay-Z told Billboard magazine that Kanye West was the inspiration for this song. He explained: "He actually sparked the idea. When he heard the beat he said, 'Man, this is just so hard! This has to be against everything - no auto-tune, none of that type of stuff!' He didn't know what I was going to do or where I was going to take it, but it was actually his fault."

Jay-Z added that the duo recorded one track with Auto-Tune previously for The Blueprint 3, but after this song came about, they decided to scrap it. He said: "After we made the 'D.O.A.' record about a month ago, we were like, 'if it's got to go, it's got to go.'"