Neanderthal genomes have been recovered from sites across Eurasia, painting an increasingly complex picture of their population structure, most of which indicates that late European Neanderthals belonged to a single metapopulation without significant evidence of population structure. Here, we report the discovery of a late Neanderthal individual, called "Thorin," from Grotte Mandrin in Mediterranean France, and its genome. These dentognathic fossils, including a rare example of distomolars, are linked to the rich archaeological record of recent Neanderthal technological traditions in the region ∼50-42 thousand years ago. Thorin's genome reveals a relatively early divergence ∼105 thousand years ago with other late Neanderthals. Thorin belonged to a population with a small group size that showed no genetic introgression with other known late European Neanderthals, revealing ∼50 thousand years of genetic isolation of his lineage, despite living in neighboring regions. These findings have important implications for resolving competing hypotheses about why Neanderthals disappeared.