Lesch-Nyhan disease (LND) is a rare genetic disorder induced by deficiency in hypoxanthine-guanine phosphoribosyltransferase (HGPRT), an enzyme of the purine salvage pathway. This leads in early age to hyperuricemia and severe neurobehavioral disturbances, including dystonia, spasticity and compulsive self-injury. To date, no treatment is available for these neurological symptoms and no animal model recapitulates all the defects observed in LND patients. Here we studied LND-related mechanisms in the fruit fly Drosophila melanogaster. We confirmed that no HGPRT activity is expressed in this organism, where the only purine-recycling enzyme is adenine phosphoribosyltransferase (Aprt). This enzyme is also present in humans but its deficiency does not trigger neurological defects. In contrast, we observed that Drosophila Aprt mutants showed both metabolic and neurobehavioral disturbances, including increased uric acid levels, locomotor reactivity impairments, sleep alterations, seizure-like behavior, reduced lifespan, and reduction of adenosine signaling and content. Locomotor defects could be rescued by neuronal Aprt re-expression in mutant context and reproduced by knocking down Aprt selectively in the protocerebral anterior medial (PAM) clusters of dopaminergic neurons, the mushroom bodies and glia subsets. Ingestion of allopurinol normalized uric acid levels in Aprt mutants but not their neurological defects, as is the case in LND patients, whereas feeding adenosine or N 6-methyladenosine during development fully rescued the epileptic behavior. Intriguingly, pan-neuronal expression of an LND-associated mutant form of human HGPRT (I42T), but not the wild-type enzyme, resulted in early locomotor defects and seizure in flies, similar to Aprt deficiency. Overall, this shows that Drosophila can be used as a new model in different ways to better understand LND and seek a cure for this dramatic disease.