Opposition MPs shouted "Where's Boris?" as a Tory MP who resigned from government over Heathrow expansion urged colleagues to join him in opposing a third runway.
Ex-trade minister Greg Hands said it was a "debate about being true to your word and to your election pledges".
Boris Johnson - who also opposes a third runway - has come under fire for travelling to Afghanistan and missing a vote to approve a new £14bn runway.
MPs are expected to back expansion.
Protesters against a third runway staged a protest in central lobby at the Houses of Parliament, a few metres from where MPs are debating the decision.
About a dozen demonstrators from Vote No Heathrow lay down on the floor with their arms outstretched before being ejected from Parliament by police.
Conservative MPs have been ordered to back a third runway, the SNP will abstain and Labour have been given a free vote, with up to 40 of them expected to back the government, meaning it will almost certainly become law.
Mr Johnson has said following Mr Hands' example and quitting the government to vote against Heathrow would "achieve absolutely nothing".
Mr Hands raised concerns over issues including flight paths and night flights and the impact on air quality, before telling the Commons: "I think this proposal is fundamentally flawed."
To shouts of "where's Boris?" from some on the Labour benches, Mr Hands said: "It's also a debate about being true to your word and to your election pledges."
In an impassioned speech, Labour's shadow chancellor John McDonnell warned that villages that had existed for 1,000 years will be "wiped off the face of the earth" to enable a company to maximise its profits.
He told MPs to remember the name of Harmondsworth resident Armelle Thomas, whose late husband Tommy arrived in the UK during World War Two to "fight for this country against fascism" by flying planes for the RAF.
Mr McDonnell said: "His home that he built up with Armelle is in the centre of what will be the runway itself.
"There are human costs to this decision that this House needs to recognise and contemplate before they vote tonight to worry and blight my community once again on a programme that will never - pardon the pun - take off."
His speech was backed by Richmond Park Conservative MP Zac Goldsmith and Lib Dem leader Sir Vince Cable, who represents Twickenham, both of whom raised concerns about the environment, the cost and alleged financial benefits of the scheme.
Conservative former transport secretary Justine Greening said the story of Heathrow was one of "broken promises, broken politics and broken economics".
Labour's shadow transport secretary Andy McDonald earlier outlined his party's official opposition to Heathrow expansion, criticising Transport Secretary Chris Grayling for making "a complete shambles of a vital national project".
He said the government's case for expansion was "riddled with gaps and fundamentally flawed".
SNP MP Alan Brown said the government had failed to give sufficient assurances that its Heathrow expansion plan would benefit Scotland's economy and "connectivity".
A new runway, which was approved by ministers earlier this month, would increase Heathrow's annual capacity from 85.5 million passengers to 130 million.
Opening debate in the House of Commons, Mr Grayling said Heathrow was "full" and a new runway was needed to secure "a clear path to our future as a global nation in the post-Brexit world."
Real reason for Johnson's mystery trip?
Analysis by BBC Political Editor Laura Kuenssberg
The mystery of his whereabouts was solved, but not yet the mystery of the purpose. Afghanistan is not exactly an easy place to head for a quick hello.
Several sources in Westminster tonight suggest there was a serious reason.
My colleague Jonathan Beale reported last month that the government was considering sending about 400 more troops to Afghanistan to join the 600 or so already there helping train Afghan forces.
Sources suggest tonight that the National Security Council will discuss the proposal tomorrow afternoon, with the government potentially approving the move, and a possible announcement in the coming days.
The soldiers would not be involved in combat, but helping the Afghans provide more security in Kabul.
Last week, Downing Street said Mr Johnson, the ex-mayor of London, would be missing Monday's vote.
His exact whereabouts, previously a matter of confusion, were revealed on Monday when the Afghan ministry of foreign affairs posted a picture on Twitter of its deputy foreign minister Hekmat Karzai meeting Mr Johnson in Kabul.
His absence has been mocked by other anti-runway campaigners in his party, including Justine Greening.
When he was elected MP for Uxbridge and South Ruislip in west London in 2015, Mr Johnson pledged to lie in front of bulldozers to stop expansion.
Before leaving for Afghanistan earlier on Monday, he wrote to constituents saying the "very considerable difficulties" facing the third runway meant it would be "a very long time before we have to make good on that pledge".
But Mr Johnson, who has long promoted a scheme for a new airport in the Thames estuary, suggested it would be a futile gesture for him to resign over the issue.
"I have long been an opponent of a third runway at Heathrow and that is why I am not voting for it tonight," he wrote.
"It is clear from what is likely to be a large majority of MPs who are in favour of a third runway that my resignation would have achieved absolutely nothing."
The government has pledged the airport will be built at no cost to the taxpayer, will create 100,000 jobs and will benefit the entire country, through guaranteed internal flights to the rest of the UK.
Ministers also insist the project will have built-in environmental protections, with the ability to fine Heathrow or ground aircraft if promises on night flights and other contentious issues are broken.
An independent review in 2015 recommended a new runway at Heathrow as the best option to address the need for extra capacity in the south of England. The Department for Transport has previously said no expansion would mean London's five airports would be full by 2034.