"One was dead on arrival and one died here this morning," said Michael Burton, a spokesman at Rowan Regional Medical Center.
The men are identified as 40-year-old Victor Eisler and 19-year-old Justin Monroe.
Burton said two other firefighters injured in Friday's blaze at Salisbury Millworks are being treated for first and second degree burns, although he said doctors don't consider their injuries to be severe.
Burton said one other firefighter injured in the blaze was sent to North Carolina Baptist Hospital in Winston-Salem for treatment. Officials there declined to comment.
City officials were set to hold a news conference Friday afternoon.
The Salisbury Post reports firefighters responded to the millworks shortly after receiving a 911 call around 7 a.m., and departments from as far away as Charlotte were called to fight the blaze.
There was little left of the millworks by early Friday afternoon. The building walls had collapsed, and smoke poured from the smoldering rubble. A steady rain helped firefighters knock down most of the flames that once towered above the site.
"We lost two firefighters today. This is a horrible day," said James Robinson, 52, of Salisbury, as he watched the fire burn. "They put their lives on the line every time they go to work. You just never know what can happen. My heart goes out to their families."