"I'm in. And I'm in to win," the former first lady who now represents New York in the Senate, said on her website on Saturday.
Clinton announced that she planned to form a exploratory committee for a presidential bid.
She is considered the front-runner. Barack Obama, the senator for Illinois, and John Edwards, the vice presidential nominee in 2004, are her main rivals.
'Hope and optimism'
"As a senator, I will spend two years doing everything in my power to limit the damage George W. Bush can do. But only a new president will be able to undo Bush's mistakes and restore our hope and optimism," Clinton said.
"I'm not just starting a campaign, though, I'm beginning a conversation with you, with America," she said.
She said she planned to host live online video conversations with voters from Monday.
Clinton would be the first female president if she won the election, and with millions of dollars in the bank, a large network of supporters and strong backing in most polls, she is seen as having a good chance of capturing the White House.
Following in Bill's footsteps
She is also the first wife of a former president to pursue the office. Bill Clinton served two terms in the White House from 1993-2001.
Critics have said that Hillary Clinton lacks the natural charisma of her husband and is overly cautious when many voters say they want authenticity from a candidate.
But her allies counter by citing her strengths - intelligence, depth of experience, work ethic and an immense command of policy detail.
She won a landslide victory when she stood for the Senate for the first time in 2000, despite being criticised for standing in a state where she had never lived.
In the Senate, Clinton has quickly moved to establish herself as someone who can work with Republicans or Democrats, often sponsoring high-profile legislation with Republican colleagues.
Recently, she has toughened her criticism of the conduct of the war in Iraq and Bush's handling of the conflict but her vote for the use of force in 2002 remains a significant political hurdle with some voters.