In 1952 He received a BA in English and Political Science from the New York State College for Teachers (now the University at Albany). Following graduation he joined the U.S. Navy where he served as a Lieutenant Junior Grade aboard a minesweeper and also worked at NATO Headquarters Naples, Italy.

After three years he left the Navy and joined Governor W. Averell Harriman as a writer and researcher. In 1960 Persico joined the United States Information Agency working in Argentina, Brazil, and Washington as a Foreign Service Officer.

From 1963 until 1966, he served as Executive Assistant to the New York State Health Commissioner and in 1966 became the chief speechwriter for then Governor of New York Nelson A. Rockefeller. He remained Rockefeller's primary speechwriter throughout the latter's Vice Presidency.

In 1977, following the end of Rockefeller's tenure, Persico published My Enemy My Brother: Men and Days of Gettysburg, an historical work of non fiction covering the American Civil War.

In 1979 he published a novel, The Spiderweb, and a further nonfiction study, Piercing the Reich: The Penetration of Nazi Germany by American Secret Agents During World War II.

Three years later he produced, The Imperial Rockefeller, a biography of his former employer. This was followed by a Biography of Edward R. Murrow. In 1995 He co-wrote Colin L. Powell's autobiography.

Throughout the 1990s, Persico continued to produce historical books (Casey: From the OSS to the CIA and Nuremberg: Infamy on Trial) as well as numerous articles on American history.

In November 2001 he published Roosevelt's Secret War: FDR and World War II Espionage and in 2004, Eleventh Month, Eleventh Day, Eleventh Hour: Armistice Day, 1918, World War I and Its Violent Climax.