Currently, there are no medications that effectively treat the core symptoms of Autism Spectrum Disorder (ASD). We recently found that the bacterial species Lactobacillus (L.) reuteri reverses social deficits in maternal high-fat-diet offspring. However, whether the effect of L. reuteri on social behavior is generalizable to other ASD models and its mechanism(s) of action remains unknown. Here, we found that treatment with L. reuteri selectively rescues social deficits in genetic, environmental, and idiopathic ASD models. Interestingly, the effects of L. reuteri on social behavior are not mediated by restoring the composition of the host’s gut microbiome, which is altered in all of these ASD models. Instead, L. reuteri acts in a vagus nerve-dependent manner and rescues social interaction-induced synaptic plasticity in the ventral tegmental area of ASD mice, but not in oxytocin receptor-deficient mice. Collectively, treatment with L. reuteri emerges as promising non-invasive microbial-based avenue to combat ASD-related social dysfunction. Display omitted •Treatment with L. reuteri rescues social deficits in several ASD mouse models•L. reuteri reverses social deficits via the vagus nerve•L. reuteri reverses social deficits even in germ-free mice•OXTR inhibition prevents L. reuteri’s effects on social behavior and VTA plasticity Precision microbial-based therapy rescues social deficits in genetic, environmental, and idiopathic mouse models of ASD. This rescue depends upon the vagus nerve as well as the oxytocinergic and dopaminergic signaling in the brain.