Obama will sign the bill to revamp the $2.5 trillion healthcare sector and then speak at a ceremony with lawmakers, in the culmination of a year-long push that hurt his approval ratings.
Aides have described a euphoric atmosphere at the White House after the House of Representatives narrowly approved the healthcare legislation, which analysts had pronounced all but dead only a few weeks ago.
Obama put his reputation on the line and poured his energy into passing the bill, even canceling a planned trip to Indonesia and Australia.
His intense focus on the issue drew criticism from some Democrats who worried healthcare was becoming a distraction from the need to fix the economy and boost jobs.
But with a major accomplishment in hand, Obama will now be able to counter critics who have suggested he had little to show for his 14 months in office.
Still, the victory may come with a cost. Americans have been lukewarm toward healthcare reform and Republicans hope to capitalize on that in November's congressional elections, in which they hope to overturn or at least reduce Democratic majorities in the Senate and House of Representatives.
Republicans say their anger over the bill's passage may make them less likely to work with Democrats on other items such as climate change legislation and immigration reform.
The post-signing ceremony and a planned trip by Obama to Iowa on Thursday will allow him a chance to celebrate the victory and try to sell Americans on the benefits of the bill.
The overhaul will extend health coverage to 32 million Americans, expand the government health plan for the poor, impose new taxes on the wealthy and bar insurance practices like refusing cover to people with pre-existing medical conditions.
It marks the biggest change in the system since the Medicare health program for the elderly was created in 1965 and fulfills a goal that eluded many of Obama's predecessors for a century, most recently including Bill Clinton in 1994.
White House spokesman Robert Gibbs said Obama plans to speak repeatedly about healthcare during the months ahead.
But the bill's passage will also free him to devote time to other priorities, including trying to secure congressional approval of a plan reform and tighten financial regulations.
Republicans have labeled the $940 billion healthcare a government intrusion into the economy and warn it would drive up the budget deficit.
The Senate this week is taking up a package of change proposed by the House to improve the bill.