Reaching the threshold to filibuster means the President likely won't need to veto the measure, even though opposition to the Iran deal enjoys majority support in the House and Senate.
Connecticut Sen. Richard Blumenthal, Michigan Sen. Gary Peters and Oregon Sen. Ron Wyden on Tuesday all announced in rapid fire succession they would support the deal, putting Obama at 41 votes of support in the Senate. By late Tuesday evening, Washington Sen. Maria Cantwell announced she would be the 42nd supportive Democrat, an extra buffer.
All Senate Democrats have now announced where they stand on the deal.
The Senate would need 60 votes to advance a measure rejecting the deal for a floor vote. If 41 of the Democrats who support the deal vote to filibuster, it would not reach a final vote in the Senate. Not all have pledged to do so, though they have pledged to vote with the President on the deal otherwise.
The four new Democrats' support came as another member of the party announced his opposition to the Iran deal on Tuesday. West Virginia Sen. Joe Manchin made a total of four Democrats who came out against the deal.
"Despite my serious reservations, I will reluctantly vote against a motion of disapproval because I believe that doing so will protect the credibility of the United States to hold Iran accountable to adhere to every single obligation in the [Joint Comprehensive Plan of Action]," Peters said in a statement.
"Having talked to the technical experts who will be involved with the implementation of this agreement, I have come to the conclusion that its many overlapping provisions will make it exceedingly difficult for the Iranians to build a nuclear weapon in the short term and will lengthen the time required should they choose to break their commitments and try to build one in the future," Wyden said.
"While this is not the agreement I would have accepted at the negotiating table, it is better than no deal at all," Blumenthal said.
Congress returns to Washington on Tuesday to begin a frenzied fall legislative session, which will include votes on the Iran deal before a Sept. 17 deadline.
Debate will begin in earnest on Wednesday, and Senate Majority Leader Mitch McConnell is looking to ensure it has senators' full attention. Hearings for the week have been canceled, and McConnell has asked all senators to be at their desks in the chamber as lawmakers debate the bill.
On Tuesday, the White House indicated it expects all the senators who have supported the deal to also vote to block the disapproval motion.
"We certainly would expect that those members of Congress who support the agreement to take the necessary steps in Congress to prevent Congress from undermining the agreement," White House press secretary Josh Earnest said in the daily briefing.
Both sides have been increasing their lobbying efforts on the deal. On Wednesday, Republican presidential candidates including Texas Sen. Ted Cruz and real estate mogul Donald Trump will headline an anti-Iran deal rally on Capitol Hill. And on Tuesday, former Vice President Dick Cheney delivered a fiery speech against the deal, calling it "madness.
Opponents also circulated a letter from 15 governors on Tuesday voicing their opposition to the deal and pledging to keep state-level sanctions on Iran in place. All four of the current governors running for president signed, including New Jersey Gov. Chris Christie, Ohio Gov. John Kasich, Louisiana Gov. Bobby Jindal and Wisconsin Gov. Scott Walker.
Also on Wednesday, Democratic front-runner and former Secretary of State Hillary Clinton will deliver her own speech on the Iran deal, where she's expected to unequivocally support it.
As Obama's support drew closer to 41 in the Senate, opponents of the deal began criticizing Democrats for, as they say, preventing an up-or-down vote on the deal by blocking its forward motion.
Senate Minority Leader Harry Reid's office has been waging its own campaign against that narrative, releasing statements on why the floor procedure is legitimate and noting that the Senate agreed to the plan almost unanimously.
"It would be a little ironic for now Majority Leader Mitch McConnell to express concerns about a tactic that he, himself, employed on countless occasions," Earnest said Tuesday. "The other thing that I'll point out is that the 60 vote threshold is actually one that was approved by the 98 senators who voted for the Corker-Cardin legislation back in the spring."