Pentagon chief Chuck Hagel will meet his Israeli counterpart on Monday in Tel Aviv for talks expected to focus on Syria's protracted civil war and Iran's disputed nuclear programme.
Hagel has said US military intervention in Syria would be a last resort and the discussions in Israel come as Syrian rebels suffered setbacks on the battlefield along with fresh turmoil within its leadership.
Syrian opposition chief Ahmad Moaz al-Khatib announced on Sunday that he would step down in the face of what he called world "inaction" while rebel forces were pushed back by President Bashar al-Assad's troops in Qusayr near the Lebanese border.
US secretary of state John Kerry on Sunday promised Washington would double its aid to the Syrian rebels with non-lethal military equipment but opposition leaders said they needed weapons to defeat Assad's well-armed troops.
US and Israeli officials, however, are worried that arms deliveries could fall into the hands of militant Islamists linked to Al-Qaeda, who have taken on a growing role in the Syrian conflict.
Hagel, in his first visit to the Middle East since taking over as defence secretary two months ago, was also scheduled to take a helicopter tour of the Israeli-occupied Golan Heights on Syria's frontier, officials said.
At the start of a six-day regional tour, Hagel will be putting the final touches on a major US arms deal with Israel and Gulf states that he said sends Iran a "very clear signal" that military action remains an option to stop it from going nuclear.
Asked if a multi-billion dollar arms package with Israel was designed to convey a message that a military strike remains an option, he told reporters on Sunday: "I don't think there's any question that's another very clear signal to Iran".
Before he departed Washington on Saturday, the Pentagon unveiled a preliminary arms agreement that will sell $10 billion worth of advanced missiles and aircraft to Israel, the United Arab Emirates and Saudi Arabia in a bid to counter the threat posed by Iran.
Under the deal, Israel will receive anti-radiation missiles designed to take out enemy air defences, radar for fighter jets, aerial refuelling tankers and Osprey V-22 tilt-rotor transport aircraft.
Officials said the security situation in Sinai also was expected to be on the agenda during Hagel's talks with defence minister Moshe Yaalon, President Shimon Peres and Prime Minister Benjamin Netanyahu.
On Sunday, Netanyahu vowed Israel would "exact a price" from the Gaza militants who recently launched missiles from Sinai at the southern resort city of Eilat.