Coming from a 'distinguished British aristocratic collection', Tygers at Play dates from c.1770-75 and, after having remained with a single family since it was commissioned, it was acquired by the present owners in 1962. The Sotheby's sale will be the first time it has appeared at auction.
It will be offered with an estimate of £4-6m.
Despite the title, the subjects are actually two leopard cubs. The seemingly incorrect title may reflect that the fact that for much of the 18th century, the word "tiger" or "tyger" was used as the generic term for all members of the big-cat family that were not lions.
The 3ft 4in x 4ft 2in (1.02 x 1.27m) oil on canvas was deemed the most ambitious of the four known paintings depicting leopards by Stubbs. It was part of the series of commissions the artist received to paint wild and exotic animals from the late 1760s onwards which resulted in him depicting creatures including a zebra, a kangaroo, an Indian Rhinoceros and his famous Lion and Horse series.
These works ranked among Stubbs' most popular subjects and have been reproduced in numerous prints over the years.
The painting here itself, however, has rarely been seen in public, having been exhibited only four times since its original appearance at the Royal Academy of Arts in London.