Born in Salem, Indiana, Hay was educated at Brown University (1858). He began his public career as a secretary to Abraham Lincoln at age 22, while technically a clerk in the Interior Department. At at time when most of Lincoln's cabinet were hostile to him and vying for position and influence, Hay served also as a friend, confidant and companion, as well as a performer of odd jobs. He lived in the northeast corner bedroom on the second floor of the White House then mostly called the Executive Mansion. He shared that room with his fellow secretary John G. Nicolay, who was six years older.

Hay's diary and writings during the Civil War are basic historical sources. Some have credited Hay with being the real author of President Lincoln's letter to the Widow Bixby, consoling her for the loss of her sons in the war.

John Hay was present when President Lincoln died after being shot at Ford's Theatre. Hay and John G. Nicolay wrote a formal 10-volume biography of Lincoln (Abraham Lincoln: A History, 1890) and prepared an edition of his collected works.

Portions of Hay's diaries and letters from 1861-1870, published in the book "Lincoln and the Civil War," show the President in a far more intimate light. The portrait of Abraham Lincoln is affectionate, certainly biased in Lincoln's favor, but also contains real insights and first-rate anecdotes of the homely and humorous sort that Lincoln himself so enjoyed.

Hay was named U.S. ambassador to the United Kingdom in 1897 when his friend William McKinley became President. Some of the recognition of the longstanding community of interests between that country and the United States came as a result of Hay's stay there. In August 1898, Hay was named Secretary of State and helped negotiate the Treaty of Paris (1898).

His contributions included the adoption of an Open Door Policy in China (announced on January 2, 1900) and the preparations for the Panama Canal. He negotiated the Hay-Pauncefote Treaty (1901), the Hay-Herran Treaty (1903), and the Hay-Bunau Varilla Treaty (1903), all of which were instrumental clearing the way for the construction and usage of the Canal.

In 1904, John Hay was one of the first seven chosen for membership in the American Academy of Arts and Letters.

On his passing in 1905, John Milton Hay was interred in Lake View Cemetery in Cleveland, Ohio.

He is also renowned for his comment, written in a letter to President Theodore Roosevelt, describing the Spanish-American War as a "splendid little war."

John Milton Hay appears as a character in Gore Vidal's historical novels Lincoln and Empire. He appears in the 1975 film The Wind and the Lion, a fictionalization of the Perdicaris Affair in Morocco in 1904. He was portrayed by John Huston. He is portrayed in the 1997 miniseries Rough Riders by actor and legendary United States Marine R. Lee Ermey.

Hay was a dear friend to Henry Adams, American historian and author. Hay and Adams built homes next to one another on Lafayette Square in Washington, DC, which building is now known as the Hay-Adams Hotel.

Brown University's John Hay Library housed the entire library collection from its construction in 1910 until the John D. Rockefeller, Jr. Library was built in 1964. In 1971, when physical science materials were transferred to the new Sciences Library, the John Hay Library became exclusively a repository for the Library's Special Collections.

For more information regarding John Hay, read The Five of Hearts.