"If the US, after laboriously negotiating this multilateral agreement with five other partners, were to walk away from those partners, we're on our own," Kerry told the Senate Foreign Relations Committee.
"We will have squandered the best chance we have to solve this problem through peaceful means," he was quoted as saying by Xinhua.
Iran and six major countries -- the US, Britain, China, Russia, France and Germany -- reached an agreement on the Iranian nuclear issue that will put Iran on the path of sanctions relief but more strict limits on its nuclear programme.
Many members of the US Congress have expressed deep concern about the deal, warning that Tehran could evade inspections and use the money from sanction relief to destabilise the region. Congress was in the midst of 60-day review period of the deal.
Testifying before the panel with Energy Secretary Ernest Moniz and Treasury Secretary Jack Lew, Kerry said: "The alternative to the deal we've reached isn't... a better deal, some sort of unicorn arrangement involving Iran's complete capitulation. That's a fantasy, plain and simple."
"The choice we face is between an agreement that will ensure Iran's nuclear programme is limited, rigorously scrutinised, and wholly peaceful. Or no deal at all," the US leader told senators.
Republican Senator Bob Corker, chairman of the Senate Foreign Relations Committee, blasted Kerry and said the US had been "fleeced" by Iran.
President Barack Obama had vowed to veto any congressional attempt to block the implementation of the Iran nuclear deal. It requires two-thirds approval in both the House and Senate to override the veto.