MPs will vote on expanding the west London airport on Monday, something a number of senior Tories have actively campaigned against for many years.
Ahead of the vote, Mr Hands, MP for Chelsea and Fulham, confirmed he would honouring a pledge to oppose Heathrow expansion.
He wrote on Twitter: “As the government will be whipping the vote on Monday, this means I am resigning from the government.
“It has been an honour to serve the prime minister (and her predecessor) for the last seven years and I wish the PM & the government every continuing success.”
Speaking in parliament on Thursday, Commons leader Andrea Leadsom said there would be a debate on a “motion relating to a national policy statement on airports” on Monday.