As expected, US senators fell two votes shy of the 60 needed to advance a resolution disapproving of the international accord, meaning the legislation aimed at sabotaging the deal is essentially dead.
"The Senate has spoken with a clarion voice and declared that the historic agreement to prevent Iran from obtaining a nuclear weapon will stand," Senate Minority Leader Harry Reid said after Democrats cleared the way for the accord.
Obama hailed the vote as "a victory for diplomacy, for American national security, and for the safety and security of the world."
"Going forward, we will turn to the critical work of implementing and verifying this deal so that Iran cannot pursue a nuclear weapon, while pursuing a foreign policy that leaves our country -- and the world -- a safer place."
Four Democrats including Chuck Schumer, the party's likely Senate leader in 2017 once Reid retires, opposed the accord, joining all 54 Republicans.
But the 58-42 vote in favor of disapproval was not enough to get over the 60-vote procedural hurdle.
The result effectively assures that the deal will go into force while sparing Obama the embarrassment of having to use his veto pen against a disapproval resolution.
But Republicans, who unanimously oppose the accord, vowed to keep fighting, with House Speaker John Boehner insisting "this debate is far from over."
Boehner said House Republicans will "use every tool at our disposal to stop, slow and delay this agreement from being fully implemented," including suing the president to prevent him from carrying out the Iran accord.
"That is an option that is very possible," Boehner told reporters Thursday.
The deal struck between Iran and six world powers provides Tehran relief from crippling economic sanctions in exchange for tight limits on its nuclear program.
Republicans complain the deal does not do away with the program altogether, fails to provide for spot inspections of nuclear sites or force Iran to end support for militant groups like Palestinian Islamist movement Hamas.
If Congress voted to disapprove of the deal, and then overrode a certain Obama veto, Congress could have prevented the White House from lifting sanctions on Iran, a scenario that would have triggered the deal's collapse.
"We are making a terrible mistake," Republican Senator Marco Rubio, a 2016 presidential candidate, said on the Senate floor, adding that he hoped there was still time to scupper the accord.
But if not, he said, he hoped the person who succeeds Obama in the White House in early 2017 will.
"I pray that on their first day in office they reverse this deal" and reimpose economic sanctions on Iran, Rubio said.
Another Republican presidential contender, Senator Lindsey Graham, issued a blistering warning to Democrats.
"I cannot believe you made the biggest miscalculation in modern history by empowering a religious fanatic with the ability to attack our nation, destroy our friends in Israel and keep the Mideast on fire for 15 years," Graham said.
"What are you all thinking?"
- 'Stunning victory' -
Under legislation that Obama signed into law this year, Congress gave itself 60 days to review the July accord once all relevant documents were delivered to US lawmakers.
In the US House, conservatives have begun pressing the case that Obama broke that law by not providing the texts of secret so-called "side deals" to the accord.
On Thursday the House passed a measure finding that the president violated the Iran Nuclear Agreement Review Act, and that the 60-day review had therefore not begun.
On Friday the House votes on legislation that would prevent Obama from lifting sanctions on Iran, and on approval of the Iran agreement, a move that forces Democrats to put their support for the accord on the record, which Republicans think may be more costly for Obama's party.
The National Iranian American Council applauded the Senate vote as "a stunning victory for supporters of peace and diplomacy."
AIPAC, the powerful pro-Israel lobby in Washington, called Obama's win "a dangerous moment for America and our allies."
"The Joint Comprehensive Plan of Action (JCPOA) will not block Iran's path to a bomb, but will enrich and entrench the world's leading state sponsor of terror," AIPAC said.