The comment was immediately decried and after a series of attempts to clear up his words, Spicer apologized in an exclusive interview with CNN's Wolf Blitzer.
"I was obviously trying to make a point about the heinous acts that Assad had made against his own people last week, using chemical weapons and gas. Frankly, I mistakenly made an inappropriate and insensitive reference to the Holocaust, for which there is no comparison," Spicer said. "And for that I apologize. It was a mistake to do that."
Spicer, who said he was "aware" that gas chambers were used during the Holocaust, later said he should have "stayed focused" on Assad and asked people to forgive him for his "mistake."
"My goal now and then is to stay focused on Assad and I should have," he said. "I realized that I had made a mistake and I didn't want to be a distraction to the President's agenda."
While Hitler did not use chemical weapons on the battlefield, Hitler and the Nazis used gas chambers to exterminate Jews, disabled people and others.
"You had someone who was despicable as Hitler who didn't even sink to using chemical weapons," Spicer said during the briefing. "So you have to, if you are Russia, ask yourself is this a country and a regime that you want to align yourself with."
The comment immediately reverberated online and audible gasps could be heard in the press briefing room after the Spicer made the comment.
Spicer, asked later in the briefing for a clarification by a reporter about the comments that Hitler did not use chemical weapons, said: "I think when you come to sarin gas, he was not using the gas on his own people the same way that Assad is doing."
Reporters in the briefing room offered the Holocaust as an example of chemical weapons use.
"He brought them into the Holocaust centers, I understand that," Spicer said.
"But in the way that Assad used them, where he went into towns and dropped them down to innocent in the middle of towns," he added, defending his statement. "I appreciate the clarification, that was not the intent."
The comment did not clear up the controversy, especially considering Spicer seemingly referred to concentration camps as "the Holocaust center."
In a statement issued after the briefing, Spicer said "in no way was I trying to lessen the horrendous nature of the Holocaust."
"I was trying to draw a distinction of the tactic of using airplanes to drop chemical weapons on population centers. Any attack on innocent people is reprehensible and inexcusable," he said.
Spicer later confirmed to CNN that he also spoke with the office of GOP megadonor and casino magnate Sheldon Adelson. Spicer spoke with Andy Abboud, Adelson's top political adviser, after his office reached out to the White House press secretary.
"It was a private conversation," Spicer said.
The majority of historians believe Nazi Germany did not ever use chemical weapons on the battlefield in the Second World War despite possessing both WWI-era chemical weapons as well as more advanced nerve agents. Hitler himself was exposed to mustard gas during his WWI service, but he did not sign off on chemical weapons use against Allied forces even when Germany was suffering battlefield losses.
However, Hitler did of course use chemical gas to murder innocent civilians in concentration camps.
"Even in WWII chemical weapons were not used on the battlefield. Even in the Korean War, they were not used on battlefields. Since WWI there's been an international convention on this," said Defense Secretary James Mattis, later in the day during a Pentagon press briefing.
The United States Holocaust Museum in Washington quickly responded to Spicer tweeting: "WATCH: Footage from our collection shows what US forces discovered when they liberated #Buchenwald."
And Chelsea Clinton, the former first daughter, tweeted: "I hope @PressSec takes time to visit @HolocaustMuseum. It's a few blocks away."
The comment comes as Jewish people all over the world are celebrating Passover. The White House hosted a Seder dinner on Monday night.
Speaking on CNN's "New Day" Wednesday, Steven Goldstein, the executive director of the Anne Frank Center for Mutual Respect, labeled Spicer's comment "a mistake" and held that he "should not be the spokesperson for the President."
"He's got to leave," said Goldstein. "President Trump has got to fire Sean Spicer."
Pointing to Spicer's multiple attempts to apologize, Goldstein said none of them merited forgiveness.
"Let me explain why we can't accept his apology," Goldstein said. "It took him three attempts to finally -- sort of -- get it right."
House Minority Leader Nancy Pelosi also called for Spicer's dismissal.
"While Jewish families across America celebrate Passover, the chief spokesman of this White House is downplaying the horror of the Holocaust," she said in a statement. "Sean Spicer must be fired, and the President must immediately disavow his spokesman's statements."