The central nervous system is a master regulator of peripheral homeostasis and cellular-stress responses; however, the contexts for which this regulatory capability evolved remain unknown. The olfactory sensory nervous system has access to privileged information about environmental conditions and can signal to the periphery to prepare for potential metabolic perturbations. The unfolded protein response of the mitochondria (UPRMT) is upregulated upon infection by many pathogens and in metabolic flux, and pathogenic infection and metabolic byproducts are a present hazard in consuming nutrients. Therefore, we asked whether the olfactory nervous system inC. elegansregulates the UPRMTcell nonautonomously. We found that loss of a single olfactory neuron pair, AWC, led to robust induction of the UPRMTdownstream of enhanced, serotonin-dependent mitophagy. Further, AWC ablation confers resistance to the pathogenic bacteriaPseudomonas aeruginosapartially dependent on the UPRMTtranscription factoratfs-1, and fully dependent on mitophagy machinerypdr-1/Parkin. These data demonstrate a novel role for the olfactory nervous system in regulating whole-organism mitochondrial dynamics, perhaps in preparation for postprandial metabolic stress or pathogenic infection.