In a surprise decision, Defence Minister Sylvie Goulard announced on Tuesday she was resigning over a fake jobs scandal that has hit her small centrist MoDem party, which allied with Macron's party in the presidential and legislative elections.
Macron accepted her resignation and said he "respected" Goulard's decision.
Her high-profile departure came after the president on Monday asked a close ally, Richard Ferrand, to leave his post as minister for territorial cohesion for a senior role in their Republic on the Move (REM) party.
Ferrand is under investigation over claims he favoured his wife in a lucrative property deal with a public health insurance fund when he headed the company.
Goulard's MoDem party is facing a preliminary probe into claims it misused European Parliament expenses in the hiring of parliamentary assistants.
The minister, who was a member of the European Parliament from 2009 to May this year, said she could not remain in the government while facing a possible investigation.
Meanwhile Macron has been carrying out a partial reshuffle of his month-old government following parliamentary elections on Sunday that handed him and his MoDem allies a commanding majority.
Macron's REM party crushed its rivals by winning 308 seats in the 577-seat National Assembly and will not need the support of MoDem, which won 42 seats, to get legislation through parliament.
Confidence in politicians
Goulard had been named to the defence job only a month ago following Macron's election to the presidency.
She said the possibility of an investigation made it impossible for her to stay in the post given Macron's pledge to clean up politics after a series of scandals involving ministers under his Socialist predecessor Francois Hollande.
"The president is committed to restoring confidence in public office, reforming France and relaunching Europe," Goulard said in a statement.
"This reform agenda must take precedence over any personal considerations.
"That is why I have asked the president, with the agreement of the prime minister, to leave the government," she added.
Paris prosecutors opened a preliminary investigation this month into claims in the Canard Enchaine newspaper that the MoDem party was using European parliamentary funds to pay assistants based in France.
Marine Le Pen's far-right National Front party is facing similar accusations.
MoDem leader Francois Bayrou was a key backer of Macron's movement during the presidential campaign, and his support was crucial in lending legitimacy to a candidate who had never before stood for elected office.
Bayrou, whom Macron named justice minister as a reward for his support, dismissed the claims last week, saying there had "never been" fake jobs among his party's European Parliament staff.
On Tuesday, the MoDem leader told AFP he would not comment on Goulard's resignation except to say her decision was "personal".
Macron is set to introduce an ethics law after the presidential candidate of the conservative Republicans, Francois Fillon, was charged with allegedly paying his wife Penelope and their children around 900,000 euros ($1 billion) to work for him in parliament.
The president has banned the newly elected REM lawmakers from employing family members.
Prime Minister Edouard Philippe is expected to name his new cabinet on Wednesday.
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