Officials portrayed Secretary of State Rex Tillerson's trip to Cairo, Kuwait City, Amman, Beirut and Ankara as a chance to build on US-led successes against the Islamic State group.
But it comes as Syrian and Russian forces step up strikes against rebel-held enclaves, Turkey battles US-backed Kurdish forces for a foothold in the north, and US-led forces bombed pro-regime fighters attacking their local allies in the east.
The State Department said Tillerson would travel to the region between February 11 and 16.
In Kuwait, he will attend a meeting of the "Global Coalition to Defeat ISIS," the first gathering at this level since US-backed local forces drove the jihadist group out of its Syrian bastion Raqa, a statement said.
"The secretary and his counterparts will discuss how the 74-member global coalition can ensure an enduring defeat for ISIS in Iraq and Syria," spokeswoman Heather Nauert said.
Iraq has declared its territory liberated from the Islamic State group, but about 2,000 US troops remain in Syria supporting a mainly Kurdish militia that controls part of the east of the country.
These Kurdish forces are now under attack from both Washington's NATO ally Turkey and by Syria's Russian-backed regime.
This week US forces helped repel an attack by government forces in the eastern province of Deir Ezzor, reportedly killing around 100 pro-regime fighters in air and artillery strikes.
The chaos in Syria will no doubt be on Tillerson's agenda in Turkey and Egypt, but he will also visit Lebanon for talks with senior leaders ahead of general elections set for May 6.
Tillerson will meet with Lebanese President Michel Aoun, Prime Minister Saad Hariri and Speaker of Parliament Nabih Berri.
"The secretary's visit will emphasize US support for the Lebanese people and the Lebanese Armed Forces," Nauert said.
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