Victor Toledo, a 75-year-old prominent environmentalist, is "a first-class professional, but he is in poor health," Lopez Obrador, who came to power in December 2018, said as he announced the latest departure.
Toledo opposes the use of glyphosate, which is classified as "probably carcinogenic" by the World Health Organization.
The government has said it will gradually reduce imports of the herbicide.
Toledo found himself embroiled in controversy last month after media reported a leaked conversation with other officials in which he purportedly criticized "contradictions" by Lopez Obrador.
"We're not going to be able to move to agroecology (a sustainable food system) freely because the president, the agriculture minister and the president's chief of staff are against all this," he reportedly said.
Lopez Obrador, however, said that Toledo had already informed him before the controversy erupted that he intended to resign.
"Not all of us are made to resist pressure," said the president, who tapped Welfare Minister Maria Luisa Albores to fill the post.
Toledo is the second environment minister to step down since Lopez Obrador took office vowing a pro-austerity and anti-corruption drive.
The left-wing populist also lost a communications and transport minister, Javier Jimenez Espriu, who opposed his decision to put control of the ports and customs in the hands of the military.
Last year, Carlos Urzua openly criticized the government when he quit as finance minister over what he called "disagreements" with Lopez Obrador.
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