Senators Richard Blumenthal of Connecticut, Ron Wyden of Oregon and Gary Peters of Michigan announced Tuesday they would support the deal, bringing the total number of senators who back the accord to 41.
That level of support would potentially block passage of a disapproval resolution against the agreement in Congress by paving the way for a filibuster of Republican attempts to reject it.
The announcement was unexpected because all three senators had been critical of the deal since its announcement in July.
The lawmakers were also highly influenced by the Israel’s opposition to the agreement. Blumenthal and Wyden are Jewish and Peters has close ties to Michigan's Jewish community.
The latest development is a major victory for Obama who has been advocating for the deal in the face of united Republican opposition.
However, 38 senators had already expressed their support, enough to sustain Obama's veto of any congressional resolution disapproving of the agreement if the Senate and House of Representatives pass such a measure.
Congress has until September 17 to vote on the nuclear deal.
Senator Harry Reid, the Democratic minority leader in the Senate, also defended the deal on Tuesday during a speech at the Carnegie Endowment for International Peace in Washington.
"There is no such thing as a better deal. There is no plausible alternative. There is no better deal," Reid said at the foreign-policy think tank.
Many American lawmakers that oppose the deal have said the United States and other world powers should return to the negotiating table to push for a tougher agreement because the current one offers significant sanctions relief in exchange for small concessions from Iran on its nuclear program.
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