The anti-establishment consumer advocate made the announcement in a televised interview on Sunday.
Mr Nader was accused by many Democrats of handing the presidency to George W Bush in the November 2000 elections. He ran again unsuccessfully in 2004.
Senators Barack Obama and Hillary Clinton are vying for the Democratic ticket. John McCain is almost certain to run for the Republicans.
Nearly three million Americans - more than 2% of the vote - backed him when he stood as the Green Party candidate in the 2000 presidential election.
That election was so close that a small proportion of those votes - particularly in the key state of Florida - would have put Al Gore in the White House.
"I'm running for president," Mr Nader said as he announced the move on the NBC's Meet the Press.
He said most Americans were disenchanted with the Democratic and Republican parties - and denied he was seeking to be a spoiler candidate.
If the Democrats cannot win by a "landslide" this year, he said, "they should just close down".
Mr Nader was born in Connecticut in 1934 and was educated at Princeton and Harvard universities.
He has spent most of his life fighting for consumers and workers against corporations.
In the 1960s his work on car safety led directly to seat belts and shatter-resistant glass being fitted in every American car. From the 1970s he built a reputation for dealing with issues including workers' rights, public safety, the environment and the influence of corporations.
He founded a number of groups including Public Citizen, which in recent years has been active in organising protests against the World Trade Organization and World Bank/IMF.