After meeting King Abdullah and other Saudis in Riyadh on Friday, Clinton was to consult with her counterparts from Saudi Arabia and its five Gulf Arab neighbours, all of them US allies.
Not only does Washington suspect Iran of funneling weapons to Syrian President Bashar Al-Assad to crush anti-government protests, it also fears Iran is both a potential nuclear weapons and missile threat to countries in the region.
Raising security ties from a bilateral to a regional level, Clinton is breaking new ground here as she will join the first strategic cooperation forum between the United States and the six-country Gulf Cooperation Council (GCC).
"We're looking to develop a regional missile defence architecture," a senior US State Department official told reporters traveling from Washington to Riyadh, adding the issue will likely come up in the GCC talks.
"No one nation can protect itself. It needs to rely on its partners in order to have an effective missile defence system," the official said on condition of anonymity.
Iran, he said, "is clearly one of the most significant threats that these nations face in the region," and he described a missile defence system as a "priority for our partnership with the GCC countries."
The Sunni Muslim-led Gulf Arab states are extremely wary of non-Arab Shiite Muslim Iran.
In Clinton's talks with King Abdullah, Saudi Foreign Minister Prince Saud Al-Faisal and others, the two sides discussed ways to tighten the sanctions on Iran over its nuclear programme, another State Department official said.
"They talked about keeping the global oil supply strong, and the essential role Saudi Arabia plays in that," the official said.
The world's largest oil producer faces Western appeals to boost output to make up for shortfalls when European countries are due to stop importing Iranian oil in June as part of tougher sanctions agreed in recent months.
Officials said Clinton also briefed the Saudis on a diplomatic opening with Iran, which said it expects to resume talks on April 13 over its nuclear programme with the United States, Russia, China, Britain, France and Germany.
Western countries fear Iran's uranium enrichment programme conceals plans to build a nuclear bomb, but Tehran insists it is only for peaceful purposes.
Clinton also discussed with the Saudis international efforts to send more humanitarian aid into Syria, and support opposition efforts to present a united and inclusive political vision for the future.
They also discussed tightening the array of US, European, Canadian, Arab and Turkish sanctions on Syria, and making sure that countries follow through on their commitments to fully impose the measures.
One official said the US and Saudi sides also discussed "reform in the kingdom, including the role of women," tackling issues that have been at the heart of the protest movements sweeping other Arab countries since last year.
US officials expected the GCC countries to discuss preparations for the Friends of Syria meeting in Istanbul on Sunday which is expected to draw ministers from dozens of Arab and Western countries.
But there are differences over how to help the Syrian people in their bid for democracy.
Saudi Arabia and its neighbour Qatar have called for arming the opposition, which includes the Free Syrian Army, made up of Syrian military defectors.
An Arab league summit in Baghdad on Thursday rejected the option of arming any side, and called on all parties to engage in a "serious national dialogue."
The United States and Turkey have agreed on the need to provide communications and other non-lethal aid to the opposition.