Pope learned the newspaper business from his father, Generoso Pope Sr., a New York political powerbroker and quarry magnate whose Italian-American newspaper interests included the Corriere d'America and the daily Il Progresso Italo-Americano. Generoso Pope Sr. had ties to New York crime boss Frank Costello, and at the birth of his son asked Costello to be the godfather. Pope Jr. took over the daily operations of the Il Progresso Italo-Americano at the age of 21 after completing his education at the Horace Mann School and the Massachusetts Institute of Technology, where he earned a bachelor's degree in general engineering in 1946 After his father died in April, 1950 at age 59, Pope worked as an intelligence officer for the CIA.
Pope acquired the New York Enquirer in 1952 for $75,000. The Enquirer purchase was supposedly made, in part, with a loan from Costello. In 1954, Pope revamped the format from a broadsheet to a tabloid, and renamed it The National Enquirer. Pope worked tirelessly throughout the 1950s and 1960s to increase the circulation of the Enquirer. In the late 50s and through to 1967 The National Enquirer was known for its gory and unsettling headlines and stories such as: "I Cut Out Her Heart and Stomped On It" (Sept. 8, 1963) [The true story of the April 1963 mutalation murder of former Olympic Skier Sonja McCaskie] & "Mom Boiled Her Baby And Ate Her" (1962). At this time the paper was sold on newsstands & drugstores only - as the gory headlines would not have been allowed in family Supermarkets, etc. Pope stated he got the idea for the format and these gory stories from seeing people congregate around auto accidents. After 1967, Pope tempered the use of gory headlines so the tabloid could be sold in a more family-friendly environment such as at supermarket check-out lines. This new sales strategy proved to be a huge boon for sales; single-copy sales of some issues (e.g. Elvis in his coffin) peaked above six million in the 1970s.
Pope moved the Enquirer from New York to Lantana, Florida in 1971. By the time of Pope's death, the National Enquirer had grown into American Media, Inc., which included the Enquirer, Weekly World News, and a magazine distributor, Distribution Services Inc.
Pope has often been described as a visionary, but has also been described with words like "zany", "eccentric", "strange", and "quirky". Rumors of mafia connections dogged him his whole career. Pope lived in a self-designed beach front home in Manalapan, Florida.
Pope was also known for his generosity. In the 1970s and 1980s, his gift to the local community was to put up the largest Christmas Tree in the world at the corporate headquarters of the National Enquirer in Lantana. The event grew into one of south Florida's most festive and celebrated traditions, but was discontinued after Pope died. He also gave back to the national community. For example, the Enquirer would profile sick kids needing medical treatment.
Pope suffered a heart attack at the age of 61 at his Manalapan mansion, and died on his way to the hospital — in an ambulance that he had donated to the town. His widow, Lois, is a well-known south Florida philanthropist, specializing in medical research, humanitarian relief, and the performing arts.