Arthur Clough was born in Liverpool to James Butler Clough, a cotton merchant of Welsh descent, and Anne Perfect, from Pontefract in Yorkshire. In 1822 the family moved to the United States, and Clough's early childhood was spent mainly in Charleston, South Carolina. In 1828 Clough and his older brother Charles returned to England to attend school in Chester. Holidays were often spent at Beaumaris. In 1829 Clough began attending Rugby School, then under Thomas Arnold, whose belief in rigorous education and lifestyles he accepted. (See Muscular Christianity.) Cut off to a large degree from his family, he passed a somewhat solitary boyhood, devoted to the school and to early literary efforts in the "Rugby Magazine". In 1836 his parents returned to Liverpool, and in 1837 he won a scholarship to Balliol College, Oxford. Here his contemporaries included Benjamin Jowett, Arthur Penrhyn Stanley, John Campbell Shairp, William George Ward and Frederick Temple. Matthew Arnold, four years his junior, arrived the term after Clough had graduated. Clough and Arnold enjoyed an intense friendship in Oxford.

Oxford, in 1837, was in the full swirl of the High Church movement led by John Henry Newman. Clough was for a time influenced by this movement, but eventually rejected it. He surprised everyone by graduating from Oxford with only Second Class Honours, but won a fellowship with a tutorship at Oriel College. He became unwilling to teach the doctrines of the Church of England, as his tutorship required of him, and in 1848 he resigned the position and traveled to Paris, where he witnessed the revolution of 1848. Returning to England in a state of euphoria, he wrote his long poem "The Bothie of Tober-na-Vuolich", a farewell to the academic life, following it up with poems from his time as student and tutor, in the shared publication "Ambarvalia". In 1849, he witnessed another revolution, the siege of the Roman Republic, which inspired another long poem, "Amours de Voyage" (reprinted by Persephone Books in 2009). "Easter Day", written in Naples, was a passionate denial of the Resurrection and the fore-runner of the unfinished poem "Dipsychus".

Since 1846, Clough had been financially responsible for his mother and sister (following the death of his father and younger brother and the marriage of his elder brother). In the autumn of 1849, to provide for them, he became principal of University Hall, a hostel for Unitarian students at University College, London, but found its ideology as oppressive as that which he had left behind in Oxford. He soon found that he disliked London, in spite of the friendship of Thomas Carlyle and his wife Jane Welsh Carlyle.

A prospect of a post in Sydney led him to engage himself to Blanche Mary Shore Smith, daughter of Samuel Smith and Mary Shore (sister to William Nightingale) but when that failed to materialize, he travelled in 1852 to Cambridge, Massachusetts, encouraged by Ralph Waldo Emerson. There he remained several months, lecturing and editing Plutarch for the booksellers, until in 1853 the offer of an examinership in the Education Office brought him to London once more. He married Miss Shore Smith and pursued a steady official career, diversified only by an appointment in 1856 as secretary to a commission sent to study foreign military education.

He devoted enormous energy to work as an unpaid secretarial assistant to his wife's cousin Florence Nightingale. He wrote virtually no poetry for six years.

In 1860, his health began to fail. He visited first Great Malvern and Freshwater, Isle of Wight. From April 1861, he traveled strenuously in Greece, Turkey and France, where he met up with the Tennyson family. Despite his fragile health, this Continental tour renewed a state of euphoria like that of 1848–9, and he quickly wrote the elements of his last long poem, "Mari Magno". His wife joined him on a voyage from Switzerland to Italy, where he contracted malaria.

He died in Florence on 13 November 1861. He is buried in the English Cemetery there, in a tomb that his wife and sister had Susan Horner design from Jean-François Champollion's book on Egyptian hieroglyphs. Matthew Arnold wrote the elegy of "Thyrsis" to his memory.

His youngest child was Blanche Athena Clough (1861–1960), who devoted her life to Newnham College, Cambridge, where her aunt (his sister Anne) was principal.

1. A Song of Autumn
2. Written on a Bridge
3. Across the Sea Along the Shore
4. Say Not The Struggle Naught Availeth
5. In a London Square
6. Love and Reason
7. The Thread of Truth
8. All Is Well
9. Ye Flags of Picadilly
10. Jacob’s Wives