The Arizona senator announced his plans to run Wednesday during the taping of a late-night television talk show, CBS's Late Show with David Letterman.
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He joins former New York Mayor Rudolph Giuliani and former Massachusetts Governor Mitt Romney, among others, in seeking the Republican nomination.
The 70-year-old McCain is a four-term senator and former prisoner of war in Vietnam. He lost the 2000 Republican nomination to then-Texas Governor George W. Bush.
McCain has long been considered a leading contender for the nomination, but a recent ABC News-Washington Post survey shows him trailing Giuliani by a margin of 44 percent to 21 percent.
McCain is a major supporter of President Bush's plans to send an additional 21,000 troops to Iraq to quell the sectarian violence.
Some information for this report was provided by AP.