Born to the son of a Confederate Army captain on November 6, 1861, in Crawfordsville, Mississippi, Thomas W. Gregory graduated from Southwestern Presbyterian University in Clarkesville, Tennessee, in 1883. Studying law at the University of Virginia, Gregory earned his degree from the University of Texas in 1885 and served as Austin assistant city attorney between 1891 and 1894. Gregory became involved in national politics while a delegate to the Democratic national conventions of 1904 and 1912. President Wilson brought him into the Justice Department, appointing him special assistant to Attorney General James McReynolds.

Following McReynolds' resignation, Wilson named Gregory attorney general on August 29, 1914. In that capacity, Gregory prosecuted violators of American neutrality before World War I; enforced the sedition, espionage, sabotage, and trading-with-the-enemy acts; reformed the federal prison administration; and advised Wilson at the Versailles Peace Conference.

Before he resigned in March 1919, Gregory declined a seat on the U.S. Supreme Court in 1916 because of a hearing ailment. Following his tenure in the cabinet, Gregory practiced law in Washington, D.C., and Houston, Texas. He died on February 26, 1933, in New York City.