De Luc came from an Italian family, which had moved to Switzerland from Tuscany in the 15th century; he was born in the Swiss lakeside city of Geneva. He initially concentrated on commercial activities with science as a side line but, in 1773, after the collapse of his business, he moved to England where he devoted himself to science. He was appointed as reader to Queen Charlotte retaining that post until his death.

In a series of letters Sur l'histoire de la terre (On the History of the Earth) addressed to Queen Charlotte in 1779, James Hutton in 1790, and Johann Blumenbach in 1798, De Luc, following in the tradition of Thomas Burnet, tried to write a history of the Earth that took account of the advances in geology yet was still compatible with the Creation as described in Genesis.

De Luc proposed that the Earth itself was old though the flood was recent. The flood was caused by a collapse of the existing lands causing their inundation by the oceans and the emergence of the present continents. As these had been the prediluvial ocean floor it was only reasonable to suppose that they should contain marine fossils. De Luc thus explained one of the puzzles facing early geologists – the presence of marine fossils in the center of continents.

De Luc opposed Hutton's fluvial theory that such major terrestrial features as valleys are the result of the still continuing action of the rivers. He pointed out that many valleys contain no rivers, that rivers far from eroding actually deposit material, and that there seems to be no relation between the size of the river and the valley it is supposed to have created. His main objection was over downstream lakes, for in this case, when the enormous amount of material eroded from the valley is considered, De Luc argued that the lake should have been filled in long before. Hutton's unsatisfactory answer was that such infilling does take place but that the lakes are much younger than the rivers. This issue was not finally resolved until the crucial role of glaciation was established by Louis Agassiz some fifty years later.

De Luc was also a major figure in meteorological research. His two works, Recherches sur la modification de l'atmosphère (1772; Studies on Atmospheric Change) and Idées sur la météorologie (1786–87; Thoughts on Meteorology), made important suggestions for advances in instrumental design. His most important achievement was his formula, in 1791, for converting barometric readings into height, which provided the first accurate measurements of mountain heights.