State media did not give a reason for the sudden decision, announced in a presidential decree that designated water resources minister Hussein Arnous as Khamis' successor.
But Syria has been in the throes of an economic crisis, with the currency plunging to record lows in recent days, aggravating hardships for ordinary Syrians battered by years of war.
The country's currency hit a record 3,000 Syrian pounds to the dollar earlier this week in an accelerating free-fall. It traded at 47 pounds at the start of the conflict.
Syrian authorities blame Western sanctions for widespread hardship among ordinary residents, where the currency collapse has led to soaring prices and people struggling to afford food and basic supplies.
The government has criticized a wave of new, tighter US sanctions, known as the Caesar Act, which takes effect later this month which economists and politicians say will further tighten the noose around Assad's government.
Arnous, 67, currently minister of water resources, was born in Idlib and had served in a long succession of government posts, including governor of Deir Zor province that borders Iraq and Quneitra province in southern Syria.
In the last year alone the Syrian pound has lost over 80% of its value, amid expanded US and European sanctions and a financial crisis in Lebanon that choked an important source of foreign currency.
With growing public anger, hundreds of protesters in the mainly Druze-inhabited city of Sweida in southern Syria took to the streets this week against worsening living conditions.
In rare demonstrations in government-controlled areas that did not rise against Assad's rule at the outset of Syria's war, protesters called for the president's overthrow.They echoed chants at the start of pro-democracy protests in 2011 that were violently crushed by security forces and sparked the violent nine-year-old conflict.