Hollis was an unsuccessful candidate for Congressional election in 1900 and an unsuccessful Democratic candidate for Governor of New Hampshire in 1902 and 1904. He was elected to the U.S. Senate for the term beginning March 4, 1913, and served from March 13, 1913, until March 3, 1919; he declined to be a candidate for renomination in 1918. While in the Senate he was chairman of the Committee on Enrolled Bills.
From 1914 to 1919, Hollis was a regent of the Smithsonian Institution, and in 1918 was United States representative to the Interallied War Finance Council. He was a member of the United States Liquidation Commission for France and England in 1919 and commenced the practice of international law that year. He was appointed to the International Bank of Bulgaria in 1922.