In 1739 Lacaille was appointed professor of mathematics in the Mazarin College, Paris, and in 1741 was admitted to the Academy of Sciences. He led an expedition (1750–54) to the Cape of Good Hope, where he determined in only two years' time the positions of nearly 10,000 stars—many still referred to by his catalog numbers. His observations from South Africa of the Moon, Venus, and Mars, in conjunction with similar observations already made in the Northern Hemisphere, led to the calculation of more accurate values for the distances of these bodies.

Before leaving the Cape, Lacaille measured the first arc of a meridian in South Africa. After his return to France in 1754, he laboured alone in compiling his data, and overwork apparently hastened his death. His Coelum Australe Stelliferum (“Star Catalog of the Southern Sky”) was published in 1763.