Excessive trial-by-trial and inter-individual neural variability of sensory responses are hallmarks of atypical sensory processing in autistic individuals with cascading effects on other core autism symptoms. The neurobiological substrate of this exaggerated variability is unknown. Here, by recording neocortical single neuron activity in a well-established mouse model of autism, we characterized atypical sensory processing and probed the role of endogenous noise sources as a driver for response variability. The analysis of sensory stimulus evoked activity and spontaneous dynamics, as well as neuronal features, reveals a complex phenotype composed of both cellular and circuit alterations. Neocortical sensory information processing in autistic animals is more variable, unreliable, and temporally imprecise. This increased trial-by-trial and inter-neuronal response variability is strongly related with key endogenous noise features. We provide a novel preclinical framework for understanding the sources of endogenous noise and its contribution to core symptoms in autism, and for testing the functional consequences for mechanism-based manipulation of this noise.