The girl's name has not been released.
Mayor Dennis Williams had to take a moment to compose himself while speaking at a news conference.
"I'm so upset that the young lady lost her life today. Things like this shouldn't happen. My heart bleeds for the family, the kids that go to this school, administrators and our city," he said.
WPVI-TV, ABC7's sister station in Philadelphia, was outside Howard High School of Technology in the 400 block of East 12th Street as medics performed CPR on the victim, who was taken on a stretcher to a waiting state police helicopter.
WPVI-TV was told that the 15-year-old girl was airlifted to A.I. duPont Hospital for Children, where she was pronounced dead.
Students at the school have told WPVI-TV reporter Chad Pradelli that the fight was over a boy, and that the girl was fighting with another girl in a bathroom when she was jumped.
Kayla Wilson said she was in a stall when the fight broke out.
"She was fighting a girl, and then that's when all these other girls started banking her, like jumping her, and she hit her head on the sink," Wilson said.
Witness tells me the Howard HS sophomore was fighting another girl in bathroom when she got jumped. pic.twitter.com/R2MNkYYjuz— Chad Pradelli (@chadpradelli) April 21, 2016
Witness tells me fight was one on one then others jumped victim. Victim hit head on sink then lost consciousness. pic.twitter.com/cKEOB8OvJp— Chad Pradelli (@chadpradelli) April 21, 2016
Parents and guardians rushed to the scene as school administrators tried to keep calm outside. At the time, many were unaware of the severity of the situation.
"Saying there was an incident that took place here at Howard and to come get your child," said Dupree Wright.
"They said there was a fight, I don't know. I am just trying to find my grandson," said Denise Dinkins.
All classes at the school have been canceled for the rest of the day and students have been dismissed.
Howard High School of Technology is a vocational-technical high school, and it is the oldest of four high schools within the New Castle County Vocational-Technical School District.