Following his term of office, Knox resumed the practice of law in Pittsburgh.
In 1916, Knox was elected by popular vote to the Senate from Pennsylvania for the first time, after passage of the Seventeenth Amendment providing for such popular elections.
He served from 1917 until his death in 1921.
While a Senator, he was highly critical of the Treaty of Versailles ending World War I, saying "this Treaty does not spell peace but war — war more woeful and devastating than the one we have but now closed".

At the 1920 Republican National Convention, Knox was considered a potential compromise candidate who could unite the progressive and conservative factions of the party.
Many thought that California Senator Hiram Johnson would release his delegates to back his friend Knox, but Johnson never did.
Warren G. Harding instead emerged as the compromise candidate, and Harding went on to win the 1920 election.
After the election, Knox urged President Harding to consider Andrew Mellon for the position of Secretary of the Treasury, and Mellon ultimately took the position.

In April 1921, he introduced a Senate resolution to bring a formal end to American involvement in World War I. It was combined with a similar House resolution to create the Knox–Porter Resolution, signed by President Warren G. Harding on July 2.
Following his term of office, Knox resumed the practice of law in Pittsburgh. In 1916, Knox was elected by popular vote to the Senate from Pennsylvania for the first time, after passage of the Seventeenth Amendment providing for such popular elections. He served from 1917 until his death in 1921. While a Senator, he was highly critical of the Treaty of Versailles ending World War I, saying "this Treaty does not spell peace but war — war more woeful and devastating than the one we have but now closed".
At the 1920 Republican National Convention, Knox was considered a potential compromise candidate who could unite the progressive and conservative factions of the party. Many thought that California Senator Hiram Johnson would release his delegates to back his friend Knox, but Johnson never did. Warren G. Harding instead emerged as the compromise candidate, and Harding went on to win the 1920 election. After the election, Knox urged President Harding to consider Andrew Mellon for the position of Secretary of the Treasury, and Mellon ultimately took the position.
In April 1921, he introduced a Senate resolution to bring a formal end to American involvement in World War I. It was combined with a similar House resolution to create the Knox–Porter Resolution, signed by President Warren G. Harding on July 2.
Philander C. Knox