Cortical circuit dysfunction is thought to contribute to schizophrenia pathophysiology and normalization of cortical circuit activity is a proposed biomarker for antipsychotic efficacy. CBD exhibits potential as an adjunctive antipsychotic therapy, however, potential sex effects on drug interactions are unknown. Spontaneous activity of primary cortical neuron cultures derived from male and female methylazoxymethanol acetate (MAM) schizophrenia model rats was recorded at baseline and following drug treatment. At baseline, only male MAM neurons exhibited increased burst firing compared to controls. CBD induced a rapid but transient increase in neuronal activity in MAM networks that was more pronounced in females. ILO and CBD individually induced time-dependent elevations in neuronal activity and when combined, ILO augmented the effects of CBD on neuronal activity in males, whereas in females drug-induced increases in activity were lost. These findings show that CBD induces rapid increases in cortical neuronal activity with sex-specific drug interactions upon ILO cotreatment.