While directing a smelting establishment in Lycoming County, Pennsylvania, Walters produced the first iron manufactured from mineral coal in the United States.

[4] In 1841, he moved to Baltimore, where he worked as a grain merchant and, in 1847, became a liquor wholesaler by establishing the importing firm of William T. Walters & Co.[4] He spent much of the American Civil War in Europe, where he studied and purchased art.

[5] With his success in business secured, Walters turned to art collection, purchasing contemporary American and European works.

[4] From 1874 onwards, Walters opened his house in Mount Vernon Place to the public most springs, with a 50 cent entrance fee;[citation needed] all proceeds went to charity.

Together, they were the parents of two children that survived to adulthood, a son and daughter: Ellen died young of pneumonia, contracted when they were traveling in England, in 1862.