Fry was a leader of the "Old Guard" faction of conservative Republicans, exerting his weight on such important committees as Rules, Foreign Relations, Appropriations, and Commerce.

He also supported high tariffs, expansion that sought additional territory and the canal connecting the Atlantic and Pacific.

President William McKinley appointed him to the peace commission that negotiated the end of the Spanish-American war.

Frye resigned as president pro tempore due to ill health a couple of months before his death.

Electing his successor proved difficult for the Senate, as the Republicans, then in the majority, were split between progressive and conservative factions, each promoting its own candidate.

Senator Frye was a charter member of the District of Columbia Society of the Sons of the American Revolution when it was founded in 1890.

The Sen. William P. Frye House near Bates College in Lewiston is on the National Historic Register.