Agriculture minister George Eustice has resigned over Theresa May's decision to allow a vote on delaying Brexit if her deal is rejected again by MPs.
In his resignation letter to the prime minister, Mr Eustice said he wants to be "free to participate in the critical debate that will take place in the weeks ahead".
The MP for Camborne and Redruth in Cornwall said he fears events in Parliament this week "will lead to a series of events culminating in the EU dictating the terms of any extension requested and the final humiliation of our country".
It comes after Mrs May promised MPs votes on a no-deal Brexit or a delay to leaving, if the Commons once again rejects her EU withdrawal agreement.
The PM vowed to give MPs the chance to express their consent for either outcome should they vote down her revised Brexit deal, which she has pledged to bring back to the Commons by 12 March.
Last month, MPs overwhelmingly rejected her agreement with Brussels and - if this were to happen again - they will now get a vote on whether to support the UK leaving the EU without a divorce deal by 13 March.
If the Commons rejects a no-deal Brexit, which is likely, MPs will then get a vote on a "short, limited extension" to the Article 50 period by 14 March.
This would postpone Brexit beyond the UK's scheduled departure date of 29 March, although Mrs May argued a "one-off" extension to the Article 50 period - the two-year period for negotiating Britain's exit which began in March 2017 - could only last to the end of June.
Mr Eustice said he would vote for Mrs May's deal when it comes back before MPs, but added that Britain should not be fearful of leaving without a deal.
Accusing Brussels of failing to conduct the exit negotiations "honourably", he added: "If the position of Parliament is now that we will refuse to leave without an agreement then we are somewhat stuck.
"This is uncomfortable for everyone, but we cannot negotiate a successful Brexit unless we are prepared to walk through the door.
"We must therefore have the courage, if necessary, to reclaim our freedom first and talk afterwards.
"We must be ready to face down the European Union here and now.
"The absence of an agreement poses risks and costs for them too."