Early in Williston's career, from 1888 to 1889 he worked as the private secretary to U.S. Supreme Court Justice Horace Gray. In the summer of 1889, he helped to collate laws from various U.S. states in order to help formulate the state constitutions of North Dakota and South Dakota.
From 1895 to 1938, Williston was a law professor at Harvard Law School, and in 1910, he briefly served as acting dean. Amongst his most important contributions at this time were the drafting of four laws aimed at providing national commerce with a legally uniform architecture. The Uniform Laws of Sales (1906), Warehouse Receipts (1906), Bills of Lading (1909), and Stock Transfers (1909) would in fact serve as precedents for the construction of the Uniform Commercial Code some decades later.
He became a consultant for the Boston law firm Hale & Dorr from 1938 to 1956, during which time he was engaged in some Supreme Court cases such as Kneeland v. AT&T and Chase National Bank v. Sayles. Williston unsuccessfully argued for the defense in the case of Boston & Maine Railroad v. Hooker before the U.S. Supreme Court on December 10 and 11, 1913.
Williston wrote 5 volumes of his legal treatise, "The Law of Contracts", which was first published during the span of 1920 to 1922. The treatise was widely acclaimed as the foremost authority on the topic and was later enlarged in 1938. In 1932, Williston served as reporter for the First Restatement of Contracts, a highly influential publication in the legal community.
In 1929, Williston was honored with the very first American Bar Association medal for "conspicuous service to American jurisprudence."
In a 1963 Harvard Law Review essay (76 Harv. L. Rev. 1321.) titled "Samuel Williston: An Inadequate Tribute to a Beloved Teacher", Justice Felix Frankfurter, lauded Williston as being the "greatest artist in teaching."