After his father's death in 1942, Annenberg took over the family businesses, making successes out of some that had been failing. He bought additional print media as well as radio and television stations, resulting in great success. One of his most prominent successes was the creation of TV Guide in 1952, which he started against the advice of his financial advisors. He also created Seventeen magazine. During the 1970s, TV Guide was making a $600,000 to $1,000,000 profit per week.
While Annenberg ran his publishing empire as a business, he was not afraid to use it for his political purposes. One of his publications, The Philadelphia Inquirer, was influential in ridding Philadelphia of its largely corrupt city government in 1949. It campaigned for the Marshall Plan following World War II. and attacked McCarthyism in the 1950s.
In 1966, Annenberg used The Inquirer to cast doubt on the candidacy of Democrat Milton Shapp for governor of Pennsylvania. Shapp was highly critical of the proposed merger of the Pennsylvania Railroad with the New York Central Railroad and was pushing the US Interstate Commerce Commission to prevent it from occurring. Annenberg, who was the biggest individual stockholder of the Pennsylvania Railroad, wanted to see the merger succeed (which it did) and he was frustrated with Shapp's opposition. During a press conference, an Inquirer reporter asked Shapp if he had ever been a patient in a mental hospital. Never having been in one, Shapp simply said "no." The next day, a five-column front page Inquirer headline read, "Shapp Denies Mental Institution Stay." Shapp and others have attributed his loss of the election to Annenberg's newspaper.