The strong words by the chief US diplomat come despite signals from her president, Barack Obama, that the US was seeking ways to hold talks with Iran as part of a new direction in Washington's foreign policy.
Clinton's remarks to reporters came after Iran's supreme leader said Obama was pursuing the same "wrong path" as George Bush, his predecessor, in supporting Israel.
Ayatollah Ali Khamenei made his comments on Wednesday at the beginning of a two-day summit in Tehran in support of Gaza and the Palestinians.
"Even the new president of the United States who came to power with the motto of changing the Bush administration's policies talks about unconditional commitment to secure Israel," Khamenei said.
"This is defending terrorism by a government."
The US has long called on Iran to end its support for organisations such as Lebanon's Hezbollah and the Palestinian Hamas faction, both of which Washington considers "terrorist" organisations.
But Iran says that Hamas is fighting an illegal occupation by Israel on Palestinian land.
In rare criticism of US ally Israel on Wednesday, Clinton said Israel's plans to demolish dozens of Palestinian homes in occupied East Jerusalem were "unhelpful".
In a news conference with Mahmoud Abbas, the Palestinian president, in Ramallah, she said the demolition indicated Israel was not committed to its obligations towards the road map peace plan.
"It is an issue that we intend to raise with the government of Israel and the government at the municipal level in Jerusalem," she said.