Claiming September's vote on whether to support the deal carries similar weight to the 2002 decision to invade Iraq, Obama suggested the soundtrack to both historic moments was the "drumbeat of war."
And he charged that Republicans who have vowed to defeat the agreement were making "common cause" with hardliners in Iran.
The unanswered question is whether that framing -- viewed even by some supporters of the deal as overly simplistic -- will be effective in swaying enough votes in Congress to, at a minimum, sustain a veto on any measure objecting to the accord.
"I don't think that aids the cause," Sen. Angus King, an independent who caucuses with Democrats and came out in favor of the deal Wednesday, said of Obama's "common cause" language. "In fact, I think there are Republicans that are really thinking hard about this agreement. I was talking to one this afternoon. And I don't think it helps."
Republicans certainly weren't pleased by what they heard.
Senate Majority Leader Mitch McConnell called on the President to "retract his bizarre and preposterous comments."
The Kentucky Republican said in statement that "members of both parties have serious and heartfelt concerns about the Iran deal," and those on both sides of the aisle "deserved serious answers today, not some outrageous attempt to equate their search for answers with supporting chants of 'Death to America.'"
He also concluded that those Obama needs most -- fellow Democrats -- would be alienated rather than reassured. "I imagine the Democrats who've already come out against this agreement will be especially insulted by it," he said.
Senate Foreign Relations Committee Chairman Bob Corker, a Tennessee Republican, said soon after Obama's speech that he was "disappointed" by Obama's remarks and his attempt to turn the Iran deal into a partisan issue when there's concern on both sides of the aisle.
He particularly objected to Obama's equating a rejection of the deal to "this straw man that says it's about war."
While Obama might contend that the choice is between war and peace, Corker pointed out that U.S. military officials have offered a different assessment.
"In testimony, the officials that have sat at the table with the President have never ever ... said that if this deal doesn't work out, would there be military action," Corker said. Instead, he continued, they've said that "it's likely that all our European partners would stay with us because they value our relationship more."
And in a direct jab at Obama, Corker added, "I think everyone in the U.S. knows that this President is not going to carry out military action against Iran. Iran knows that."
The evocation of the Iraq vote, however, seemed to be targeted primarily at Democrats. The decision to approve the invasion was one many in his party -- including his vice president and both secretaries of state -- supported at the time but eventually came to regret.
Casting that vote as a mistake whose aftermath is still being felt, Obama said a decision in opposition of his Iran deal could carry similar consequences.
"I raise this recent history because now more than ever, we need clear thinking in our foreign policy, and I raise this history because it bears directly on how we respond to the Iranian nuclear program," he said.
But that decision, according to those who made it a decade ago, came amid a vastly different political environment -- and isn't necessarily analogous to the choice facing lawmakers today.
"I voted against sending our troops to the Iraq war, and that was an unpopular vote," said Maryland Sen. Ben Cardin, the top Democrat on the Senate Foreign Relations Committee. His support is highly sought by the White House, but so far he has remained undecided.
The American public in 2015 is "much more divided" over entering into a nuclear pact with Iran than it was about going to war with Iraq, Cardin said. Several polls have shown that a majority of Americans want Congress to vote down the agreement.
"At the end of the day, it's not what's popular, it's not what the President of the United States is asking us to do, it's what's in the best interest of America, and that's how I'll judge it," he said.
Cardin and other Democrats have been the focus of an intense lobbying campaign by the White House to back the deal -- an effort to garner friendly votes almost unheard of during Obama's tenure.
The President has invited them to the White House for personal briefings, pressed them over the phone and took three Democratic congressmen golfing on a scorching Sunday afternoon in July.
Many Democrats who complained they were being ignored by the White House during the first six years of the Obama administration say they've been impressed by the outreach.
But it remains to be seen whether Obama's appeal Wednesday and the strident arguments he's embraced in making his case will win over those in his party wrestling with how to vote.
In the hours after Obama's speech, at least five House Democrats said they would support the plan, including Mike Thompson of California, Jim McGovern of Massachusetts, Mark Pocan of Wisconsin and Earl Blumenauer and Peter DeFazio of Oregon.
But several key Democratic senators -- including Chuck Schumer of New York, Ben Cardin of Maryland, Mark Warner of Virginia and John Tester of Montana -- have said they still need time to assess the agreement.
Ben Rhodes, Obama's deputy national security adviser, said the administration was confident its framing of the deal would persuade Democrats to Obama's side.
"We're used to some reflexive partisanship on these issues," Rhodes said. "We're expecting there to be very strong Republican opposition, as there has been on many of our foreign and domestic priorities, but we're confident there's a growing base of support among Democrats in both the House and Senate for this deal."