Hands said he had no choice but to quit after Prime Minister Teresa May issued an instruction to Conservative MPs to vote in favour of a multi-billion dollar third runway at Britain's biggest airport.
Hands announced his decision on his social media site, saying: "As the government will be whipping the vote on Monday, this means I am resigning from the government. I wrote to the PM earlier this week on how I will honour these 2017 general election pledges to the people of Chelsea and Fulham and vote against the Heathrow third runway."
The Conservative politician, who has pledged to honour his fight against the project, announced his resignation ahead of a vital debate in the House of Commons next week, Xinhua news agency reported.
The Independent newspaper said his decision will be a big blow to May, who had tasked Hands with piloting a vital Brexit trade bill through Parliament in the coming weeks.
The daily said Hands' decision will also pile pressure on Foreign Secretary Boris Johnson, a fierce critic of the Heathrow expansion.
Johnson will miss the vote on Monday as he will be out of the country. Although Hands has resigned as a minister he will continue to serve as a backbench MP in the House of Commons, representing his London constituency.
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