Five years later, Congress chartered the Second Bank of the United States, which was directed for most of the period 1816 to 1836 by Nicholas Biddle, the nation's first chief banker and scion of the city's most iconic family.

The real estate bust of the late 1970s, accompanied by high interest rates and rates of foreclosure, did not hurt PNB to the extent it did its more highly exposed crosstown rival, First Pennsylvania, which never completely recovered from the temporary collapse of the real estate investment trust (REIT) industry and was eventually purchased by PNB in 1990.

Meanwhile, Corestates Bank of Delaware would focus on lending to the many corporations, including chemical giant DuPont, headquartered in the low-tax First State just south of the Pennsylvania border.

George W. Strawbridge Jr., a Campbell Soup Company director, heir to the Strawbridge & Clothier department store fortune, and major shareholder in Meridian Bancorp, became director and largest individual shareholder in the Corestates Corporation, continuing an ongoing marriage between the bank and one of the region's most iconic companies, the Campbell Soup Company, that had in the 1970s made G. Morris Dorrance Jr., scion of the Campbell clan and prominent Gladwyne, Pennsylvania, socialite, PNB's board chairman.

In the rash of regional bank takeovers that occurred near the end of the twentieth century, CoreStates was then acquired by First Union Corporation of Charlotte, North Carolina, in 1998.

Wachovia Bank, suffering losses during the financial crisis of 2007–2008, was acquired by Wells Fargo, headquartered in San Francisco, California.

First Pennsylvania Bank's Centre Square twin office towers, with their iconic Clothespin sculpture by Claes Oldenburg, shifted the center of that district west at its opening in 1976.

In 1973, the bank opened a second Center City office complex on Independence Mall at Fifth and Market Streets that became headquarters for its operations divisions.