Samuel Griffin combined legal practice in Virginia with military and political service during the Revolution and early republic. As an officer attached to Charles Lee, he was wounded in the New York campaign of 1776. While recovering near Philadelphia, he took command of a mixed force of militia and regulars sent into New Jersey to distract British troops. His movements around Mount Holly drew Colonel Carl von Donop away from Trenton shortly before Washington's attack there in December.

Returning to Virginia, Griffin served on the state's Board of War and as mayor of Williamsburg during the later war years. These posts involved civil administration as well as the problems of defending a state increasingly exposed to British operations. After the war he resumed legal and political work. Williamsburg voters sent him to the House of Delegates, where he served from 1786 to 1788 before entering Congress.

Griffin represented Virginia in the first three United States Congresses, from March 1789 to March 1795. He served during the establishment of federal institutions and early party divisions. Congressional classifications identify him alternately with administration supporters and opponents, reflecting the unsettled alignments of those years. His district included Williamsburg and neighboring communities, although its number changed after reapportionment. He did not serve in Congress after 1795. His career linked revolutionary operations with state and federal government.