DeBartolo grew up in a family famous for real estate development. She attended Saint Mary's College of Indiana. After graduation, she joined the family business, The DeBartolo Corporation, and became its executive vice president. In 1994, following her father's death, she became company chairman. Since acquiring the firm, she has diversified its assets, buying several retail and restaurant chains.
In 1981, The DeBartolo Corporation purchased the National Hockey League's Pittsburgh Penguins. DeBartolo York was president of the Penguins from 1988–1991, including their 1990–1991 championship season, and is therefore one of only eight women to have her name engraved on the Stanley Cup. In 1991, the year following the championship, The DeBartolo Corporation sold the Penguins.
In 2000, DeBartolo York and her husband John York gained control of the 49ers and other sporting assets from her brother, Edward J. DeBartolo Jr. In 1998, Eddie DeBartolo Jr. was linked to the investigation of former Louisiana governor Edwin Edwards for corruption and tax fraud, and was suspended from active control of the team by the National Football League. The Yorks, as co-owners of the team, assumed control of the franchise, and after two years of lawsuits were granted permanent ownership.
She currently resides in the Youngstown suburb of Canfield, Ohio.