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.

In 1960, Persico joined the United States Information Agency working in Argentina, Brazil, and Washington as a Foreign Service Officer.

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.

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.