"No one should escalate this conflict. We've been engaged in intense diplomacy with allies and partners, communicating that message directly to Iran. We communicated that message directly to Israel," Blinken told reporters.
Iran has vowed a response after Israel was suspected of killing Hamas political leader Ismail Haniyeh in Tehran.
President Joe Biden has hinted at frustration with Israeli Prime Minister Benjamin Netanyahu over the assassination, which came just as he hoped to make progress in talks to reach a ceasefire in the 10-month Gaza war.
"Our commitment to Israel's security is ironclad. We will continue to defend Israel against attacks from terrorist groups or their sponsors, just as we'll continue to defend our troops," Blinken said.
"But everyone in the region should understand that further attacks only perpetuate conflict, instability, insecurity for everyone," he added.
Blinken, speaking after talks with the Australian foreign and defense ministers at the US Naval Academy in Annapolis, Maryland said the United States was working "intensely to de-escalate tensions in the Middle East and to prevent a spread of conflict."
Blinken spoke earlier in the day by telephone to Jordanian Foreign Minister Ayman Safadi.
Jordan -- in a delicate spot with its large Palestinian population and peace treaty with Israel -- played a key role in an earlier showdown in April in helping the United States shoot down Iranian missiles and drones, ensuring minimal damage in Israel.
Safadi on Sunday traveled to Tehran to discuss the situation. Blinken declined to answer directly on whether Jordan would again support action against an Iranian attack, saying only that US partners wanted an end to conflict.
"Further attacks only raise the risk of dangerous outcomes that no one can predict and no one can fully control," Blinken said.
"It's urgent that everyone in the region take stock of the situation, understand the risk of miscalculation and make decisions that will calm tensions, not exacerbate them."
On Monday, suspected pro-Iranian Shiite fighters wounded seven US personnel in rocket fire on a base in western Iraq.
"Make no mistake, the United States will not tolerate attacks on our personnel in the region," Defense Secretary Lloyd Austin told the news conference in Annapolis.
The Biden administration, which has sent additional forces into the Middle East, had been hoping to focus not on an escalating crisis but on a ceasefire plan for Gaza.
Hamas on Tuesday named Yahya Sinwar, an alleged mastermind of the October 7 assault on Gaza who is believed to be hiding in tunnels, to be its new political chief to succeed the slain Haniyeh.
Blinken played down the impact of appointing a man on the top of Israel's target list, saying Sinwar has always been "the primary decider."
"This only underscores the fact that it is really on him to decide whether to move forward with a ceasefire that manifestly will help so many Palestinians in desperate need," Blinken said.
