Autism spectrum disorder (ASD) is a pervasive neurodevelopmental condition with heterogeneous phenotype. Here, we investigated prefrontal cortex (PFC) alterations and cerebellum-PFC connectivity in the IB2 KO mouse model of ASD. Significant alterations in signal processing and plasticity have been reported in the cerebellar granular layer of IB2 KO mice, confirming the crucial cerebellar involvement in ASD pathophysiology. Given the PFC renowned role in ASD and its functional connections with the cerebellum, we explored the prelimbic cortex (PrL) microcircuitry in IB2 KO and WT mice at different levels. Ex vivo investigations in the PrL of IB2 KO mice revealed: i) disrupted E/I balance in favor of excitation in layer 5 (L5) columns using voltage-sensitive dye imaging; ii) increased excitability and E/I ratio, together with enhanced NMDA receptor-mediated postsynaptic currents in L5 pyramidal neurons using whole-cell patch-clamp recordings. In vivo single unit (SU) recordings of putative PrL pyramidal neurons in anesthetized mice were performed to characterize spontaneous activity and responses to electrical stimulation of the cerebellar dentate nucleus (DN). IB2 KO SUs showed lower basal firing frequency and a reduced response to DN stimulation. Interestingly, blocking inhibition had a stronger impact on KO than WT on basal frequency, responses to DN stimulation, and interspike-interval distribution. These results suggest that the PrL neuron hyperexcitability might be compensated in vivo by mechanisms boosting the inhibitory modulation. However, further investigations are warranted to investigate the balance between primary and compensatory changes in the PrL of IB2 KO mice.