He was born at Clopton House, just outside Stratford-upon-Avon, Warwickshire. His ancestors had been owners of Clopton manor since Henry III's time. His father, John de Clopton, received a license to erect an oratory in the manor-house in 1450, and his elder brother, Thomas, obtained permission from Pope Sixtus IV in 1474 to add a chapel for the celebration of divine service. 
Hugh, a younger son, left Clopton at an early age, and rapidly became a wealthy mercer in London. He was Sheriff of London in 1486, when Sir Henry Colet was mayor, and was himself chosen mayor in 1492, when he was apparently knighted. His vast fortune enabled him, it is said, to become possessed of the family estates at Clopton, the inheritance of his elder brother, and it is certain that the neighbouring town, of Stratford was his favourite place of residence. About 1483, he erected there (in Chapel Street) 'a pretty house of brick and timber,' which was ultimately purchased by Shakespeare in 1597, and was, in a renovated form, the poet's residence, under the name of New Place, until his death in 1616. 
The nave of the chapel of the Stratford guild of the Holy Trinity, situated opposite his 'pretty house,' Clopton rebuilt, and he adorned the building with a steeple tower, glass windows, and paintings for the ceiling. He also removed at his own expense the old wooden bridge over the River Avon, and substituted a remarkably fine stone structure resting on fourteen arches. Clopton's chapel and Clopton Bridge are still notable features of modern Stratford. 
He died 15 Sept, 1497. 
By his will, dated a week earlier, he provided for the due completion of the Stratford improvements, and left a hundred marks to twenty-four maidens of the town, and £200. for rebuilding the cross aisle of the parish church. He also instituted exhibitions of £4. a year each for five years for three poor scholars at each university of Oxford and Cambridge ; and gave £10. to the common box of the Mercers' Company, and other sums to 'the Venturers' fellowship resident in Zeland, Brabant, and Flanders,' and to 'the fellowship of the staple of Calais.' 
Clopton desired to be buried in the parish church of Stratford, if he died in that town, where he spent much time in his later years. But his death took place in his London house, in the parish of St Margaret Lothbury, and he finally 'bequeathed ' his body to the church of that parish. Clopton never married.
The Clopton estates ultimately passed to Joyce (not Anne as is sometimes stated) Clopton, of the sixth generation in descent from Thomas, Sir Hugh's elder brother. She married Sir George Carew, 1st Earl of Totnes, who thus became for a time master of the property.