DeBartolo went on to earn a degree in civil engineering at the University of Notre Dame. Next came a decade of construction jobs with his stepfather. Capitalizing on his engineering skills, DeBartolo found himself serving in the Army Corps of Engineers during World War II. It was during the War, in 1944, that he married Marie Patricia Montani and incorporated his own company, The Edward J. DeBartolo Corporation.

The family also owned the Pittsburgh Penguins of the National Hockey League from February 1977 until selling it to an ownership group led by Howard Baldwin in November 1991. His team would win the Stanley Cup in 1991. He would be engraved onto the Stanley Cup along with his daughter Denise DeBartolo York. DeBartolo said at a rally after the first win that the occasion "possibly the happiest moment of my life." He also owned the soccer team Pittsburgh Spirit from 1978 until 1986.

While DeBartolo was unsuccessful in his attempt to purchase the Chicago White Sox in 1980, he owned and developed three thoroughbred racetracks – Thistledown in Cleveland, Remington Park in Oklahoma City, and Louisiana Downs in Bossier City, Louisiana.

DeBartolo founded the Pittsburgh Maulers of the United States Football League in March 1983, but folded the team after the first season (1984) when the league announced it would move to a fall schedule, the same time as the NFL's Pittsburgh Steelers.

In 1988, he partnered with Dillard's Department Stores to buy Higbee's of Cleveland, Ohio. In 1992, william Dillard, founder of Dillard's, bought DeBartolo's share, except for the property interest in Higbee's Public Square flagship store in Cleveland (sold to Tower City in 2001), and renamed it the Higbee chain. DeBartolo's idea of a Retail real estate developer going forward with new projects easily and quickly, by virtue of anchor stores which he owned, would never become a reality.

The Edward J. DeBartolo Corporation was the undisputed leader in the shopping mall industry from the birth of the industry until DeBartolo's death, owning almost one-tenth of all mall space in the United States. DeBartolo also branched out into other types of urban development and construction, such as hotels, office parks, and condominiums. He established a work ethic of fifteen-hour days and seven-day weeks. He once told his senior executives, "My wife has never seen me lie down while the sun was up." By 1990, DeBartolo was estimated to have more than $1.4 billion in personal wealth.

As a result of several years' impaired cash flow, DeBartolo prepared to take his company public as a real estate investment trust or "REIT". Most of DeBartolo's competitors were preparing to do the same, their operations suffering from a lack of capital in the private markets. In late 1993, the two largest shopping center companies at the time, DeBartolo and Simon were coming to the market simultaneously. Their advisors informed them that the capital markets could not absorb that much equity; either one of them must back down or prices would suffer severely. DeBartolo agreed to withdraw. In April, 1994, most of the properties owned by The Edward J. DeBartolo Corporation were transferred to DeBartolo Realty Corporation, a public REIT, in its initial public offering. The new company was chaired by Edward J. DeBartolo Jr.; DeBartolo Sr. was unwilling to deal personally with the constraints of running a public company. In 1996, DeBartolo Realty Corporation was acquired by Simon Property Group, the public REIT formed by DeBartolo's longtime competitors, Melvin and Herbert Simon.

DeBartolo died of pneumonia on December 19, 1994 in Youngstown, Ohio at the age of 85.