Bainbridge Colby was born on December 22, 1869, in St. Louis, Missouri. He went to local schools before graduating from Williams College in 1890. Colby earned a law degree from the New York Law School in 1892, the same year he was admitted to the bar and opened a New York City law practice.

In 1912, Colby walked out of the Republican national convention to support Theodore Roosevelt's bid for the presidency under the banner of the Progressive, or Bull Moose, Party. Colby himself ran as a Progressive candidate for a U.S. Senate seat from New York but was defeated in both 1914 and 1916.

Following American entrance into the First World War, President Woodrow Wilson appointed Colby to the U.S. Shipping Board; Colby later became vice president of the U.S. Shipping Board Emergency Fleet Corporation in 1917. That same year, Wilson named him to serve as U.S. delegate to the Inter-allied conference to promote cooperation between the Allies.

Following Robert Lansing's resignation as secretary of state, Wilson asked Colby to become the nation's chief diplomat. Colby accepted and remained secretary of state until the end of the Wilson administration (1920-1921). While in the cabinet, he pushed for ratification of the Versailles Treaty in the U.S. Senate.

Following the end of the Wilson administration, Colby formed a Washington, D.C., law practice with former President Wilson until he founded his own practice. He remained there until retirement in 1936.

Colby was at first a supporter of President Franklin D. Roosevelt but eventually became a critic of the New Deal, forming an anti-Roosevelt group named the American Liberty League. Bainbridge Colby died on April 11, 1950, in Bemus Point, New York.