DeBartolo grew up in a family famous for real estate development. She attended Saint Mary's College of Indiana, the Holy Cross women's counterpart to adjacent Notre Dame. 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 co-chairman and all 78 DeBartolo malls were sold.
In 1978 , Edward DeBartolo purchased the National Hockey League's Pittsburgh Penguins. and established DeBartolo York as owner and president. She presided over the Penguins 1990–1991 championship season, and was the third woman to serve as President of a Stanley Cup winning team. In 1991, the year following the championship, she sold the Penguins to assist the DeBartolo Corporation, which was facing challenges in the aftermath of the real estate collapse of 1987.
In 2000, DeBartolo York and her husband retired pathologist John York gained control of the 49ers and other sporting assets from her brother, Edward J. DeBartolo Jr.. She and her husband have since given over control of the 49ers to their son Jed.
She has four children, and lives in the Youngstown suburb of Canfield, Ohio.