There will be five days of discussion on the terms of the UK's withdrawal and future relations with the EU ahead of an expected vote next Tuesday.
The PM cancelled the original vote on 11 December as opposition from Tory MPs and Labour pointed to a heavy defeat.
She has since sought extra written assurances from the European leaders.
Ministers are expected to publish a document later offering measures aimed at easing concerns about the implications of Mrs May's plan for the future of Northern Ireland.
BBC political correspondent Vicki Young said they were understood to include giving the Northern Ireland assembly the power to vote against any new EU rules if the so-called backstop arrangement comes into force.
On the eve of Wednesday's debate, the government suffered an embarrassing defeat when 20 Tory MPs joined forces with Labour to signal their opposition to a no-deal Brexit.
A host of former ministers, including Michael Fallon, Justine Greening and Sir Oliver Letwin, voted to amend the finance bill to restrict the ability of the Treasury to make tax changes in the event of a no deal - and threatened to target other legislation in the coming months.
The UK Parliament passed legislation last year stating that the UK would leave the European Union on 29 March - two years after negotiations on its exit began.
The withdrawal agreement finalised in November includes guarantees over the rights of EU citizens living in the UK and British expats on the continent, the terms of the UK's £39bn "divorce" settlement and a proposed transition period lasting until the end of 2020.
These and other legally-binding measures will not come into force unless MPs approve the agreement and an accompanying declaration on future trade and security relations.
Before last month's vote was pulled, scores of Conservative MPs voiced their opposition to the plan and few have publicly given any signal they have changed their mind since then.
Former Brexit minister Suella Braverman told BBC's Newsnight that she could not back the plan "unless something changed democratically" and many of her colleagues felt the same way.
The Democratic Unionist Party, on whom Mrs May relies for her Commons majority, has said there is "no way" that it can vote for the agreement as it currently stands.
Its 10 MPs strongly object to the backstop, a contingency plan agreed by the UK in December 2017 which the EU has said is necessary in case the two sides do not agree their future relationship or another solution by the end of 2020.
The DUP and many Tory MPs want the backstop to be removed entirely or a legal guarantee that the UK will be able to leave it unilaterally at a time of its choosing.
Without that, they say the UK faces being bound indefinitely to EU rules, curbing its freedom to strike trade deals and result in Northern Ireland being treated differently from the rest of the UK.
The Irish government has said it is willing to give further "written guarantees" to reassure MPs that the UK will not be "trapped" - although it has said the agreement cannot be changed.
Wednesday's session, due to begin after prime minister's questions at about 13.00 BST, will be opened by Brexit Secretary Steve Barclay.
If MPs approve the procedural business motion, the debate will continue on Thursday, Friday and Monday before concluding on Tuesday, when the PM is expected to address MPs before the vote.
Mrs May has said the UK will be in "uncharted territory" if the agreement is rejected and this could put Brexit at risk - although she has not ruled out asking MPs to vote more than once.
The prime minister has said the "perfect deal" is not on offer and while it involves compromises, British firms will get tariff and quota free access to European markets, freedom of movement will end and the UK will exit the Common Agricultural Policy and Common Fisheries Policy.