Samuel Ferguson was born on 10 March 1810 in Belfast and was educated at Belfast Academy, the Royal Belfast Academical Institution and Trinity College, Dublin, where he was called to the Bar in 1838. Between 1845 and 1846 he went to Europe where he made many sketches, especially of cathedrals and churches dedicated to Irish saints and he studied painting and sculpture in Italy. Some of his sketches are in the Linen Hall Library, Belfast. He became Queen's Counsel in 1859 and Doctor of Laws in 1864. He was published in Blackwood's Magazine and in the Dublin University Magazine.

In collaboration with the Young Ireland movement he founded the Protestant Repeal Association. He kept an open house for the literati of Dublin at his home in North Great George's Street. In 1867 he became Deputy Keeper of Public Records in Ireland and published many volumes of verse, some of the poems based on Gaelic legends. His collected poems, Lays of the Western Gael, appeared in 1865, and Comgal, an epic poem in five books, in 1872. He was knighted in 1878 for his work in reorganising the Public Records.

He was President of the Royal Irish Academy and wrote many essays on Irish antiquities. He is renowned for his work Ogham Inscriptions in Ireland, Wales and Scotland that was edited by his widow. His Poems of Sir Samuel Ferguson were published in Dublin in 1963 with an introduction by Padraic Colum. He died at Howth on 9 August 1886 and was buried at Donegore, County Antrim.