A major probe into high-level graft, at a time when Ukraine is fighting against Russia for its very survival, has sparked public outrage and thrust its leadership into crisis as Washington steps up pressure on Kyiv to reach a settlement.
Yermak was leading Ukraine's effort to push back against terms proposed by the US that would satisfy many of Moscow's territorial and security demands. Zelenskiy said he would consider a replacement on Saturday.
"Russia is eager for Ukraine to make mistakes. We won't make any," Zelenskiy said on Friday in a video address, calling for greater unity.
"Our work goes on. Our struggle goes on."
Yermak has been a close friend of Zelenskiy's since the president's days as a TV comedian, and helped guide his successful outsider's campaign for election in 2019.
Since then, the 54-year-old has positioned himself as a chief decision maker, attracting criticism both at home and abroad as an unelected adviser with outsized power.
Yermak had confirmed his apartment was being searched and said he was cooperating. The National Anti-Corruption Bureau and the Specialised Anti-Corruption Prosecutor's Office did not specify which investigation the searches were linked to.
The two agencies this month unveiled a sweeping probe into an alleged $100 million kickback scheme at the state atomic energy company allegedly involving former senior officials and an ex-business partner of Zelenskiy's.
Yermak was not named as a suspect, but activists, opposition MPs and even some in Zelenskiy's own Servant of the People party had called for his dismissal, saying his presence compromised Ukraine's bargaining power.
Mykyta Poturayev, a lawmaker for the party who had called for an overhaul of both the presidential office and the government, said Yermak's resignation came at a perilous moment but had been necessary.
"The potential dangers of Andriy Yermak remaining in his position outweighed these risks," he said.
The US push for a settlement comes as Russia grinds forward on several parts of the sprawling front line, where it has mostly advanced painfully slowly and at great cost in lives since sending its troops into Ukraine in 2022.
Moscow says its troops are close to capturing the eastern city of Pokrovsk, which would be their biggest prize in nearly two years.
On Thursday, President Vladimir Putin said a 28-point US plan leaked last week could be "a basis for future agreements". But he demanded that Kyiv give up some of the strategic eastern lands that Russia claims before Moscow stops fighting.
Showing progress in fighting corruption is also a central element of Kyiv's bid for European Union membership, which Ukrainian officials see as critical to breaking out of Russia's orbit.
The two anti-graft agencies have stepped up their campaign during Russia's invasion, but have said they face pressure from vested interests.
Zelenskiy briefly rolled back their independence last July but reversed course after a public outcry and criticism from foreign partners.
