David Davis' resignation on Sunday came only two days after May had secured approval from her cabinet to negotiate "a business-friendly" deal to leave the EU.
In his resignation letter, the Secretary of State for Exiting the EU said he did not want to be a "reluctant conscript" and that he thought the plan approved on Friday "is certainly not returning control of our laws in any real sense".
May has struggled to unite factions within her ruling conservative party.
In a letter responding to Davis' resignation, she said she was "sorry" he had chosen to resign and argued her proposal was "consistent with the mandate of the referendum".
Junior Brexit Ministers Steve Baker and Suella Braverman resigned shortly after Davis.
The resignation of Davis nine months before the UK is due to leave the EU is a major blow to Prime Minister Theresa May.
