A police officer was also wounded, CBS News reported.
The controversial event was being held in Garland, a suburb of Dallas. The venue, the Curtis Culwell Center, was under lock-down as SWAT teams attempted to secure the premises.
Nearby businesses, including major chain stores, were evacuated amid reports of possible explosives in the area and a bomb squad investigated the gunmen's car.
The American Freedom Defense Initiative (AFDI) organized the event featuring far-right Dutch politician Geert Wilders, who has been outspoken against Muslims.
"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.
Muslims find depictions of the Prophet Mohammed offensive and such cartoons have triggered violent protests, including when the Danish daily Jyllands-Posten published 12 satirical cartoons in 2005, triggering deadly protests in all Muslim countries.
The cartoons were also published in French satirical weekly Charlie Hebdo, where gunmen killed 12 people in January.