In a televised address on Sunday, Arseniy Yatsenyuk said his resignation would be formally submitted to parliament on Tuesday.
"I took the decision to resign as prime minister of Ukraine," he said.
"On Tuesday, April 12, I will submit it to parliament.
"My decision is based on a several reasons - the political crisis in the government has been unleashed artificially, the desire to change one person has blinded politicians and paralysed their will to bring about real changes in the country."
Mr Yatsenyuk's Cabinet survived a no-confidence vote in February, but two parties left the governing coalition to protest the failure to oust the prime minister, who is under fire over the worsening economy and slow pace of reforms.
The withdrawal deprived the coalition of its majority in the Ukrainian parliament.
If lawmakers fail to form a new coalition and unite behind a new prime minister, that may lead to early elections, which President Petro Poroshenko has sought to avoid for fear of further destabilizing the situation in the country.
"From today I see my goals as broader than the powers of the head of the government," Mr Yatsenyuk said.
He said he would focus on passing a new electoral law, enacting constitutional and judicial reform, and ensuring "the coalition's control over the course of a new government."