Prime Minister Aristides Gomes announced his resignation in a hastily convened press conference in his office Thursday.
"I presented my resignation to the head of state. The president has not yet responded. My mandate is now in his hands," Gomes told reporters.
Last week, Guinea-Bissau's parliament passed a motion to impeach Gomes, with 54 out of 85 parliamentarians voting in favor, saying a change was needed to wrest the country out of its economic spiral.
Prior to the vote, the country's three leading political parties had signed a pact saying Gomes' government needed to be replaced. All three parties have accused Gomes of arrogance and of stonewalling the opposition, repeatedly refusing to meet with their leadership.
President Joao Bernardo "Nino" Vieira was elected last June in the first presidential vote since a 2003 military coup toppled democratically elected President Kumba Yala. He appointed his protege, Gomes, as prime minister, infuriating the main opposition party PAIGC, which called the appointment unconstitutional.
Gomes was initially supported by other key parties, but that support quickly eroded.
Under the country's constitution, once the parliament passes an impeachment motion, the president is required to sign a decree dissolving the Cabinet. On Thursday morning, reporters massed outside the gates of the presidency, awaiting a statement from Vieira, who has so far not commented on last week's impeachment vote.
Composed mostly of jungles that merge into swamps jutting into the Atlantic Ocean, Guinea-Bissau is deeply impoverished, has been wracked by coups and corruption ever since independence from Portugal in 1974.