A total of six ministers, including Foreign Minister Dmytro Kuleba, submitted their resignation and parliament accepted the resignations of four.
They included the resignations of a deputy prime minister in charge of European integration, the strategic industries minister overseeing Ukraine's arms production and two other ministers, the lawmakers said.
"We need new energy today, and these steps are related only to the strengthening of our state in different directions," Zelenskiy told media during a joint news conference with a visiting Irish Prime Minister Simon Harris.
Lawmakers said that parliament was expected to consider Kuleba's resignation on Thursday.
After Zelenskiy, 43-year-old Kuleba was the best-known face of Ukraine overseas, meeting leaders around the world and lobbying for military and political support in fluent English.