Police said two men drove up to the conference center in Garland, Texas, and began shooting at a security guard.
"Garland Police officers engaged the gunmen, who were both shot and killed," the city of Garland said in a statement.
The security guard suffered injuries that were "not life-threatening," the statement said. Wilders has also long been targeted by Islamists because of his extreme views on Islam.
"I am shocked. I just spoke for half an hour about the cartoons, Islam and freedom of speech and I had just left the premises," Wilder told AFP in an email.
"This is an attack on the liberties of all of us!" Wilders wrote. He added that he was safe with police.
The identities of the shooters has yet to be confirmed, but the SITE Intelligence Group reported that an Islamic State (IS) fighter claimed on Twitter that the shooting was carried out by two pro-IS individuals.
In a series of tweets and links, a jihadist named as Abu Hussain Al Britani, which SITE said was British IS fighter Junaid Hussain, claimed that "2 of our brothers just opened fire" at the Prophet Mohammed exhibition in Texas.
"They Thought They Was Safe In Texas From The Soldiers of The Islamic State," added the tweet.
About 200 people were inside the event, said local police spokesman Joe Harn.
Police said they suspect the gunmen's vehicle may contain an "incendiary device" and a bomb squad was on the scene.