The US State Department confirmed McGurk’s resignation, effective 31 December.
Just last week McGurk said "nobody is declaring a mission accomplished" in the battle against IS – just days before the president's surprise announcement of victory against the jihadist movement.
Trump – who postponed his holiday vacation as failed budget talks triggered a partial US government shutdown – again on Saturday said "ISIS is largely defeated."
"When I became President, ISIS was going wild," the president tweeted. "Now ISIS is largely defeated and other local countries, including Turkey, should be able to easily take care of whatever remains. We're coming home!"
McGurk, a Barack Obama appointee whom Trump kept on, reportedly said in his resignation letter that IS militants were in fact not defeated, and that prematurely withdrawing US troops could foster conditions allowing the jihadists to amass power in the region once more.
The 45 year-old top envoy was set to leave his position in February, but reportedly felt he could no longer continue in the job after Trump's declaration.
The news capped a chaotic week that saw Mattis – seen as a voice of moderation in the Trump White House – quit after telling the president he could not go along with the Syria decision.
The shock troop pullout will leave thousands of Kurdish fighters – which the Pentagon spent years training and arming against IS – vulnerable to Turkish attack.
"It would be reckless if we were just to say, 'Well, the physical caliphate is defeated, so we can just leave now,'" McGurk had told journalists earlier this month.
"I think anyone who's looked at a conflict like this would agree with that."