It happened at the store located at 13th and Market streets, one block from City Hall.
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Philadelphia police say it all began with an attempted shoplifting around 10:45 a.m.
According to investigators, the male suspect was attempting to steal several hats when he was stopped by security.
There was a confrontation, police say, but security backed off after getting the merchandise back and let the man leave.
Then, about 15 minutes later, investigators said the man came back. He approached one security guard, then turned toward the other with a knife in hand and began stabbing that guard.
The other guard intervened and was stabbed several times.
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Both victims were taken to the hospital by police where one of them was pronounced dead at 11:19 a.m.
Police tell sister station WPVI-TV the suspect fled on SEPTA and dropped a knife on SEPTA property.
The suspect was brought into custody at the Somerset station around noon and was positively identified by witnesses, Interim Police Commissioner John Stanford said.
Stanford said the guards are Macy's employees and were not armed.
The names of the guards have not been released, though police say the guard who was killed is a 30-year-old man. He died after suffering a stab wound to the neck.
The other guard is a 23-year-old man who was stabbed in the face and left arm. He is hospitalized in stable condition.
Police say one of the guards has been employed by the store for a few years, while another had worked there for just a few months.
Police news conference on fatal stabbing at Center City Macy's
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Initial reports from the scene indicated there were three stabbing victims, but police say in fact there are only two victims.
Video from WPVI's chopper showed several police vehicles and an ambulance on the scene outside the Macy's.
Ground video showed the entire area cordoned off as shoppers from the Macy's store waited outside.
Macy's is one of the locations in Center City that has been hit the hardest with retail theft. That Macy's location has filed over 250 reports of retail theft this year, Stanford said.
An investigation into this incident continues.