Reed was born on a farm in Richland County, Ohio. He moved with his family to Cedar Rapids, Iowa at the age of 3. He became a lawyer and moved to Kansas City, Missouri in 1887.

Reed served as a city councilor of Kansas City from 1897 to 1898, as prosecutor of Jackson County from 1898 to 1900, and as mayor of Kansas City from 1900 to 1904. In 1910, he was elected to the United States Senate from Missouri as a Democrat. He served in the Senate for three terms, from 1911 until 1929, when he decided to retire. In the Senate, Reed distinguished himself as an opponent of corruption and government programs that he felt would not work. Unlike many members of his party, he opposed the League of Nations and also opposed prohibition of alcohol. He tried and failed to seek the Democratic nomination for President. He served as chairman of the Committee on Weights and Measures from 1917 to 1921.

In 1929, as Reed was leading the Senate, H.L. Mencken wrote a tribute to him, praising Reed for his opposition to what Mencken called "demagogues" and "charlitans" from both political parties. Reed then retired from politics and moved back to Missouri where he continued to practice law. He died at his summer home in Oscoda County, Michigan.