Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder diagnosed in presence of impaired social communication and interaction together with restricted, repetitive repertoire of behaviours, interests, and activities. To date, available medications address comorbidities (e.g. anxiety, irritability, seizures) rather than core symptoms. The aim of the present study was to explore the therapeutic potential of foliglurax, a mGlu4 positive allosteric modulator (PAM), in relieving ASD-like behavioral features in the well validated genetic Shank3B knockout mouse model, and to assess how these effects would generalize to two additional models, the Fmr1 and Oprm1 null models. Further, to gain insight into the underlying neurobiological mechanisms, we evaluated the transcriptional effects of foliglurax treatment in brain reward regions of Shank3B-/- mice. Chronic foliglurax administration dose-dependently relieved autistic-like symptoms and excessive anxiety in Shank3B-/- mice as well as in Oprm1-/- and Fmr1-/- mice. Moreover, foliglurax showed carry-over effects up to three weeks after cessation of treatment in these three models, that were best maintained in the Fmr1 null mice. Finally, transcriptional modifications induced by mGlu4 PAM treatment in Shank3B-/- mice mostly involved actors of the glutamatergic transmission in the ventral pallidum, an emerging key node of the social reward system. Among recently developed allosteric modulators of glutamatergic receptors, foliglurax displays a promising therapeutic potential to relieve core symptoms in ASD patients. Efficacy in three mouse models with different etiologies supports high translational value.