Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder with genetic and environmental origins. Alterations in sensory disturbance have been clinically linked to socio-emotional problems in individuals with ASD but remain understudied in the research field. Recent evidence has shown that the prefrontal cortex (PFC), a brain region plays an essential role in social cognition, is involved in pain management. Hence, this study aims to qualify nociceptive response of ASD and the implication of PFC. Valproate (VPA)-exposed offspring and Tsc2 heterozygous knockout (Tsc2+/-) mice were respectively used as environmental and genetic ASD models in the present study. First, we observed that both VPA-exposed offspring and Tsc2+/- mice with social deficits exhibited hyposensitivity to thermal nociception compared with their corresponding control groups during behavioral testing. By using electrophysiological recordings, we further explored the role of PFC by applying agonists of transient receptor potential vanilloid 1 (TRPV1) and group I metabotropic glutamate receptors (mGluRs), two key synaptic mediators integrating nociceptive sensitization. The results showed that the synaptic changes were failed to induce following TRPV1 or mGluR agonist application in the PFC of two ASD models. To sum up, our findings reveal a lessened sensitivity to thermal nociceptive stimulus with abnormal PFC synaptic responses in both environmental and genetic ASD models, suggesting a potential modulatory role of PFC in thermal hyposensitivity of ASD individuals.