Ngrebada was made prime minister in February 2019. He had served as President Faustine-Archange Touadera’s chief of cabinet before the appointment.
He had been one of the main architects of the Khartoum peace agreement in February 2019 between the authorities and armed groups which brought relative stability to the country that has been mired in conflict since 2013.
A spokesman for the presidency said Ngrebada could be asked to lead a new government.
His resignation comes after strained political and diplomatic ties with former colonial ruler France.
Paris announced this week that it was suspending military assistance to Bangui, saying authorities in the African country were complicit in a Russian propaganda campaign against its forces and diplomats.
The central African Republic has since charged a French man found with weapons with espionage.
In December 2020, Facebook accused Paris and Moscow of running rival disinformation campaigns in CAR. The platform said it had pulled down more than 500 accounts, pages, and groups from Facebook and Instagram originating from Russia and France targeting 13 African countries, including Mali, Tunisia, Libya, Niger, Ivory Coast, and Burkina Faso.
Some in opposition have accused Ngrebada of forging very close links with Moscow.
Russian paramilitaries help protect Touadera’s government from rebels and also train the country’s army.
France has seen its influence in the Central African Republic wane since the entry of Russia in 2018.