From the late 19th century, Walters lived most of the time in New York City, where from 1903 on, he served on the executive committee of the Metropolitan Museum of Art.

[2] In 1889, Walters moved to Wilmington, North Carolina, to serve as general manager of his father's company, the Atlantic Coast Line Railroad.

Following his father's death in 1894, Walters was elected president of the company, and he relocated the line's headquarters from North Carolina to New York City.

In New York City, Walters lived with Pembroke and Sarah Jones, two friends he had met in Wilmington, North Carolina.

[5][6] Walters envisaged a museum that would fulfill an educational role within the community, but initially made modest additions to his father's collection.

In 1902. he undertook an acquisition on a scale unprecedented in the history of American collecting: he bought the contents of the Palazzo Accoramboni in Rome.

He enhanced the breadth of the 19th-century holdings with such early works as Ingres' The Betrothal of Raphael and the Niece of Cardinal Bibbiena,[9] bought in 1903.

Although Walters was not fond of French Impressionism, he bought two works in 1903 from American artist Mary Cassatt, including Claude Monet's Springtime.

He collected Egyptian, ancient Near Eastern, and Islamic art, as well as a number of key classical and western medieval objects.