The Pentagon is planning to withdraw up to half of the 14,000 American troops serving in Afghanistan.
A US official said the troops could be out by summer, though no final decision has been made.
President Donald Trump has long pushed to pull troops out of Afghanistan, considering the war a lost cause.
But earlier this year, he was persuaded by former defence secretary Jim Mattis and other military leaders to keep troops on the ground to pressure the Taliban and battle a stubborn Islamic State insurgency.
Officials said the latest White House push for withdrawal was another key factor in Mr Mattis's decision to resign on Thursday, along with the news of a total pull-out from Syria.
America has lost more than 2,400 soldiers and spent more than $900bn (£711 billion) in its longest war after US troops stormed Afghanistan in 2001, triggered by the 11 September attacks.
Three US presidents have pledged to bring peace to Afghanistan, either by adding or withdrawing troops, by engaging the Taliban or shunning them and by trying to combat widespread corruption in the government.
In 2014, the US and NATO formally concluded their combat mission, but American and allied troops remain, conducting strikes on the Islamic State group and the Taliban, as well as working to train and build the Afghan military.
However Taliban insurgents control nearly half of Afghanistan and are more powerful than at any time since a 2001 US-led invasion.
They carry out near-daily attacks, mainly targeting security forces and government officials.
But in recent months there have been renewed efforts to make progress on peace talks with the Taliban.
Officials now worry that withdrawing US troops could dampen those prospects and simply encourage the Taliban to wait until they can take advantage of the gaps when the forces leave.
Mr Mattis is set to leave by the end of February after two tumultuous years struggling to soften and moderate the president's hardline and sometimes sharply changing policies.
He told Mr Trump in a letter that he was leaving because "you have a right to have a Secretary of Defense whose views are better aligned with yours".
The announcement came a day after Mr Trump surprised US allies and members of Congress by announcing the withdrawal of all US troops from Syria.
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Mr Trump's decision has been criticised for abandoning America's Kurdish allies, who may well face a Turkish assault once US troops leave, and had been opposed by the Pentagon.
Mr Mattis's resignation letter did not mention the disputes over Syria and Afghanistan, but noted his "core belief" that American strength is "inextricably linked" with the nation's alliances with other countries.
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