Cyrus Griffin practiced law in Virginia after legal study in Britain and entered the House of Delegates during the Revolution. He represented Virginia in the Continental Congress from 1778 to 1780 and again in 1787–88. His public employment increasingly centered on judicial and national business. From 1780 he served on the Court of Appeals in Cases of Capture, the Confederation's tribunal for disputed maritime prizes, which heard disputes over privateering and wartime seizures.

In 1788 Congress elected Griffin its president. He was the final holder of that office under the Articles of Confederation, serving as the new Constitution was ratified and arrangements were made for the federal government's inauguration. The presidency was a congressional chairmanship, with duties different from those of the later executive president. Griffin also participated in negotiations with the Creek Nation as a commissioner in 1789.

George Washington gave him a recess appointment as the first United States district judge for Virginia in November 1789. Senate confirmation followed in February 1790. He remained on the bench until his death in 1810. The district court handled federal jurisdiction in a state whose port commerce made admiralty cases especially significant, and Griffin also sat with visiting Supreme Court justices on circuit. His experience bridged Confederation and federal institutions. He died at Yorktown and was buried in Bruton Parish churchyard at Williamsburg.