In a speech made early on Sunday morning, Lamothe said he was leaving “with a sense of accomplishment”.
“This country has undergone a deep and dynamic transformation and a real change in benefit of its people,” he said.
President Michel Martelly said earlier he accepted the findings of the commission that had recommended Lamothe’s replacement.
Protesters have been seeking Lamothe’s resignation, but many also want Martelly to step down.
Martelly has been accused by opposition groups of returning Haiti to dictatorial rule, after repeatedly delaying elections expected since 2011.
Lamothe and Martelly have blamed six opposition senators for blocking the vote. The senators say the legislation is unconstitutional and favours the government.
Martelly appointed Lamothe as prime minister in 2012, and there is now speculation that Lamothe might seek the presidency in upcoming elections.
Haiti’s capital Port-au-Prince has endured a growing number of violent demonstrations in recent weeks during which protesters have demanded the holding of elections that were expected in 2011 and the resignations of Lamothe as well as Martelly.
On Saturday, one man was found dead in a protest in Port-Au-Prince during clashes with police who fired tear gas.
It was not immediately clear how the man died, but he was shot at least once in the wrist.
Demonstrations also spread to other towns, including Gonaives and Cap-Haitien.