In 1925 Spellman became first American assistant to the papal secretariat of state. In 1931 he successfully smuggled Pius XI's Non Abbiamo Bisogno, an antifascist encyclical, out of Italy. The letter was printed and distributed by the Associated Press and United Press.

Spellman's work mobilizing American Catholics behind World War II was recognized by Pius XII, who appointed him cardinal in 1946. In 1949 he bitterly debated Eleanor Roosevelt over the merits of federal funding for parochial schools. A supporter of Senator McCarthy and later the Vietnam War, he was also a major figure in the Vatican's Second Council. Spellman repeatedly asked for the establishment of diplomatic relations with the Vatican, something which did not happen until 1984.