Brett McGurk joins defence secretary Jim Mattis in an exodus of experienced national security officials from the president’s administration.
Only 11 days ago, Mr McGurk had said it would be "reckless" to consider Isis defeated and unwise to bring American forces home.
His resignation letter was submitted on Friday to Secretary of State Mike Pompeo.
In it, Mr McGurk – who was appointed by Barack Obama in 2015 and retained by Mr Trump – said the militants were on the run, but not yet defeated, and the premature withdrawal of American soldiers would create the same conditions that gave rise to IS.
His resignation is effective from 31 December.
He said he was already planning to leave the job in mid-February after the US hosted a meeting of foreign ministers from coalition countries, but he now felt it best to resign ahead of that date.
Mr Trump is acting to pull all 2,000 US troops from Syria after declaring victory over Isis – a contradiction of his own experts' assessments. Many have called the move rash and dangerous.
Mr Mattis – perhaps the most respected foreign policy official in the administration – announced on Thursday he will leave by the end of February.
He told Mr Trump in a letter he was departing because "you have a right to have a secretary of defence whose views are better aligned with yours".
The US began air strikes in Syria in 2014 with ground troops moving in the following year to battle IS and train Syrian rebels. In a tweet this week, Mr Trump abruptly declared the mission accomplished.
Mr McGurk, 45, previously served as a deputy assistant secretary of state for Iraq and Iran, and during the negotiations for the landmark Iran nuclear deal by the Obama administration, led secret side talks with Tehran on the release of Americans imprisoned there.
He was briefly considered for the post of ambassador to Iraq after having served as a senior official covering Iraq and Afghanistan during George W Bush's administration.
Taking over temporarily will be Lt Gen Terry Wolff, who served three tours of active duty in Iraq.
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