Lawmakers voted 51-49 to open debate on the 940-page megabill, with two of Trump's fellow Republicans joining Democrats to oppose the legislation that would fund the president's top immigration, border, tax-cut and military priorities.
Trump on social media hailed the "great victory" for his "great, big, beautiful bill".
After hours of delay, during which Republican leaders and Vice President JD Vance worked behind closed doors to persuade last-minute holdouts to support the measure, Democrats demanded the megabill first be read aloud in the chamber - a task that could delay the start of the debate until Sunday afternoon.
Democrats say the bill's tax cuts would disproportionately benefit the wealthy at the expense of social programs for lower-income Americans.
Once the bill has been read, lawmakers will begin up to 20 hours of debate on the legislation. That will be followed by a marathon amendment session, known as a "vote-a-rama", before the Senate votes on passage. Lawmakers said they hoped to complete work on the bill on Monday.
Saturday's vote was in limbo for hours as Vance, Senate Majority Leader John Thune and other top Republicans sought to persuade last-minute holdouts to support the legislation.
Trump was monitoring the vote from the Oval Office late into the night, a senior White House official said.
The megabill would extend the 2017 tax cuts that were Trump's main legislative achievement during his first term as president, cut other taxes and boost spending on the military and border security.
The nonpartisan Joint Tax Committee released an analysis projecting that the Senate bill's tax provisions would reduce government revenue by $US4.5 trillion ($A6.9 trillion) over the next decade, increasing the $US36.2-trillion US government debt.
The White House said this month the legislation would reduce the annual deficit by $US1.4 trillion.
The world's richest person, Elon Musk, also took a swipe at the bill, which would end tax breaks for the electric vehicles that his automaker Tesla manufactures.
Calling the bill "utterly insane and destructive," he risked reigniting a feud with Trump that raged earlier this month, before Musk backed down from his rhetoric.
"The latest Senate draft bill will destroy millions of jobs in America and cause immense strategic harm to our country!" Musk wrote in a post on his social media platform X.
Democrats will focus their firepower with amendments aimed at reversing Republican spending cuts to programs that provide government-backed healthcare to the elderly, poor and disabled, as well as food aid to low-income families.
The bill also would raise the Treasury Department's debt ceiling by trillions of dollars to stave off a potentially disastrous default on the nation's debt in the coming months.
If the Senate passes the bill, it will then return to the House of Representatives for final passage before Trump can sign it into law. The House passed its version of the bill last month.Â
