Although several longevity regulatory pathways have been identified in a wide variety of organisms, the role of the nervous system in lifespan regulation remains largely a mystery. Here, we report that the most widely used atypical antipsychotic drug aripiprazole could robustly extend lifespan and health span of C. elegans. The lifespan extension effect of aripiprazole is dependent on AMPK/FOXO-mediated dietary restriction (DR)-like mechanism. In addition, D2-like dopamine receptor dop-2 and dop-2-coupled Go protein goa-1 are required in aripiprazole-mediated lifespan extension. DGK/PKC/PKD pathway, rather than cAMP/PKA pathway, acts as downstream of G protein and upstream of AMPK in aripiprazole-induced lifespan extension. This is the first study to reveal the lifespan extension effect of aripiprazole in lifespan regulation. As aripiprazole has good long-term safety and tolerability profile in patients, it may serve as a novel anti-aging drug and produce beneficial effects on human health and longevity. Moreover, the model of aripiprazole-mediated lifespan extension may provide a new direction for developing new anti-aging drugs