Foreign Office minister Alistair Burt, health minister Steve Brine resigned and business minister Richard Harrington announced his decision to leave the government on Twitter, according to news agency AFP.
They refused to support Theresa May over giving more say to MPs in leaving the European Union.
Around 30 members of May's Conservative party defied her to vote in favour of a motion giving MPs control of parliamentary business later this week to try to come up with an alternative Brexit plan.
Harrington in his resignation letter said that the government's approach was "playing roulette with the lives and livelihoods of the vast majority of people in this country".
"As the UK's industry minister, the clear message I have been receiving from the business community is that the failure to secure a deal and to rule out a hard Brexit is resulting in cancelled investment decisions, business being placed abroad, and a sense of ridicule for British business, across the world," Harrington wrote.
Several ministers had quit May's government overBrexit.
Last year in November, British Brexit Secretary Dominic Raab resigned. The 44-year-old was appointed to the role of Brexit minister in July last year following the resignation of his predecessor David Davis, who also quit in protest at May's Brexit strategy.