McCarthy issued a statement Friday calling the milestone a "tragic number that is reflective of the gang violence and proliferation of illegal guns that have plagued some of our neighborhoods."
The police department went back and forth Friday, first verifying the 500th killing, then backing off and saying an earlier death was still being investigated.
By late Friday, police confirmed 40-year-old Nathaniel Jackson had become the 500th homicide victim when he was fatally shot in the head outside a convenience store on the city's West Side.
The last time Chicago reached the 500-homicide mark was in 2008, when the year ended with 512 killings. City records show Chicago had 435 homicides last year.
The Cook County Medical Examiner's Office says Jackson was pronounced dead at Stroger Hospital early Friday.
Jackson's death remains under investigation. No arrests have been made.