Aside from a few portraits of friends, the Hamilton family, and British people on the Grand Tour, most of his paintings, many of which are very large, were of classical Greek and Roman subjects.

In Livy it is made later, after the overthrow of the Roman monarchy.As a painter of classical subjects, Hamilton was highly regarded by Johann Joachim Winckelmann, writer Goethe, young sculptor Antonio Canova and others in Rome.

He received a commission to paint the altar piece of Sant'Andrea degli Scozzesi, the Scottish national church in Rome, for which he portrayed the Martyrdom of St Andrew.

[3] As an art dealer and archaeologist, Hamilton undertook excavations at Hadrian's Villa in Tivoli in 1769–1771, at first to acquire marble for his sculptor to restore sculptures.

His excavators reopened the outlet of a low-lying swampy area and "after some weeks' work underground by lamp-light and up to the knees in muddy water" retrieved sculptures from the muck, where they had been thrown centuries before with timber when Christians levelled the sacred grove.

The painter advised the younger man to put aside his early, Rococo manner and concentrate on conflating the study of nature with the best of antiquities and a narrow range of classic modern sculptors.

Hamilton was successful in making generous offerings to the Vatican's Museo Pio-Clementino, as the Pope claimed one-third of all excavated works and had the right to forbid export of outstanding treasures.