Mr Obama, the senator for Illinois, has won the primary in Wisconsin, and is also projected to take victory in Hawaii - his 10th win in a row.
This puts huge pressure on Mrs Clinton to win in Ohio and Texas next month.
John McCain won Wisconsin for the Republicans, boosting his front-runner status in his party's contest.
Mr McCain is also projected to win a Republican primary in Washington state.
With 99% of precincts having reported in Wisconsin, Mr Obama had 58% of the vote to Mrs Clinton's 41%.
The state has 74 Democratic delegates at stake. The Associated Press (AP)news agency said Mr Obama was projected to win at least 38 of them, and Mrs Clinton 27, with nine still to be awarded.Hillary Clinton
13 states, 1,245 delegates
Arizona, Arkansas, California, Florida, Massachusetts, Michigan, Nevada, New Hampshire, New Jersey, New Mexico, New York, Oklahoma, Tennessee
24 states, 1,319 delegates
Alabama, Alaska, Colorado, Connecticut, Delaware, Georgia, Hawaii, Idaho, Illinois, Iowa, Kansas, Louisiana, Maine, Maryland, Minnesota, Missouri, Nebraska, North Dakota, South Carolina, Utah, Virginia, Washington state, Wisconsin
2,025 delegates needed for nomination.
8 states, 245 delegates
Alabama, Arkansas, Georgia, Iowa, Tennessee, West Virginia, Kansas, Louisiana
18 states, 942 delegates
Arizona, California, Connecticut, Delaware, Florida, Illinois, Maryland, Missouri, New Hampshire, New Jersey, New York, Oklahoma, South Carolina, Virginia, Washington state, Wisconsin
Mitt RomneyMitt Romney
11 states, 253 delegates
Alaska, Colorado, Maine, Massachusetts, Michigan, Minnesota, Montana, Nevada, North Dakota, Wyoming, Utah
1,191 delegates needed for nomination.
Meanwhile, with 51% of precincts counted in Hawaii, where the Illinois senator was born, he had taken 76% of the vote, leading AP and CNN to project victory.
The state has 20 delegates up for grabs.
The BBC's Jonathan Beale says Wisconsin was a significant victory for Mr Obama, eating into Mrs Clinton's support base.
It is a major disappointment for Mrs Clinton, the senator for New York, who had been hoping to restore momentum to her campaign.
Instead, Mr Obama was reported to have gained almost equal support from white women, and to have polled well from working-class Democrats - both groups which have usually supported Mrs Clinton.
Mr Obama also took the youth vote and six out of 10 self-described independent voters, according to exit polls for ABC.
But he and Mrs Clinton are already looking ahead to March's bigger contests in Ohio and Texas, seen by analysts as crucial to her credibility as a candidate.
Speaking at a victory rally in Houston, Texas, Mr Obama said: "The change we seek is still months and miles away and we need to get all of Texas to help us get there."
Addressing a rally in Youngstown, Ohio, Mrs Clinton said the primary campaign was "about picking a president who relies not just on words but on work - hard work to get America back to work".
Before the results from Wisconsin were calculated, Mr Obama held a slight lead over Mrs Clinton, with 1,280 delegates to her 1,218.
It will take 2,025 delegates to secure the Democratic nomination at the party's national convention this summer.
Mr McCain, the senator for Arizona, appeared to target Mr Obama in his victory speech as he promised to ensure Americans were "not deceived by an eloquent but empty call for change".
On the Republican side, the race between Mr McCain and Mike Huckabee, a former Arkansas governor, continues.
Mr McCain now has almost four times as many delegates as his main rival, Mike Huckabee.
With 99% of precincts reporting in Wisconsin, he led with 55% of the vote compared with 37% for Mr Huckabee and 5% for Texas Congressman Ron Paul. There are 40 Republican delegates at stake.
Early exit polls for AP suggested Mr McCain had made headway with some core Republican voters, beating Mr Huckabee overwhelmingly for the support of moderate Republicans.
The Washington Republican primary is the second vote in a two-part nominating contest - half its delegates were decided earlier in a caucus on 9 February, which was narrowly won by Mr McCain.
With 56% of precincts counted on Tuesday, Mr McCain had amassed 49% to Mr Huckabee's 21% and Mr Paul's 7%.
Washington state's Democrats are also holding a primary but their delegates to the party's summer nominating convention have already been chosen on the basis of caucuses.