Wetmore took night classes at George Washington University Law School, earning a degree in 1896, when his position was assistant chief clerk.

In November 1896, he was promoted to head of the Law and Records Division of the Office of the Supervising Architect, within the Treasury Department in Washington, D.C., by President Grover Cleveland.

[4][5] In June 1907, he was appointed by President Theodore Roosevelt, along with four other officials, to a special committee to "fully investigate and examine into the forms of contracts used by the various departments, bureaus and offices of the government.

He was the EO, which put him in charge of all non-technical operations of the office,[5] under Taylor, and then under his successor Oscar Wenderoth who took over in 1912.

[4] For a period in 1912 after the resignation of Taylor, Wetmore was acting supervising architect until Wenderoth relocated to Washington.

[5] Wenderoth resigned in April 1915 to return to private practice in a firm that specialized in designing bank interiors.

Although outsiders did not always understand why a lawyer was running the office, the duties were primarily administrative; supervising architects did not require him to be trained as one.

In collaboration with William Gibbs McAdoo, the Secretary of the Treasury from 1913 to 1918, buildings were to be designed with "scale, materials and finishes" that directly reflected their "location, prominence and income".

[5] A small post office with revenue of under $15,000 would be made of brick, with standard wood windows and doors and would appear "ordinary".

[8] Wetmore's name is inscribed on the cornerstones of approximately 2000 federal buildings that were designed during his tenure that spanned the administrations of Wilson, Harding, Coolidge, Hoover, and into Franklin Roosevelt's.

During World War II the Liberty ship SS James A. Wetmore was built in Brunswick, Georgia, and named in his honor.