He was admitted to the bar in 1913 and commenced practice in Richmond, Missouri, in 1914. During the First World War he enlisted in the Sixth Regiment, Missouri Infantry, on April 8, 1917. He served as captain of Company G, One Hundred and Fortieth Infantry Regiment, Thirty-fifth Division, from August 4, 1917, to May 15, 1919. He received the Purple Heart and Silver Star. He returned April 28, 1919.
Milligan was elected as a Democrat to the Sixty-sixth Congress to fill the vacancy caused by the resignation of Joshua W. Alexander and served from February 14, 1920, to March 3, 1921. He was an unsuccessful candidate for reelection in 1920 to the Sixty-seventh Congress. He later served as delegate to the Democratic National Convention in 1928.
Milligan was elected to the Sixty-eighth and to the five succeeding Congresses (March 4, 1923 – January 3, 1935). He was not a candidate for renomination in 1934, but was an unsuccessful candidate for nomination for United States Senator. He and fellow congressman John J. Cochran were defeated by Harry S. Truman. Jacob Milligan's brother Maurice M. Milligan challenged Truman in the Democratic primary for his reelection campaign in 1940.
