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Background: Exposure to Δ9-tetrahydrocannabinol (THC) is an established risk factor for later-life neuropsychiatric vulnerability, including mood- and anxiety-related symptoms. The psychotropic effects of THC on affect and anxiogenic behavioral phenomena are known to target the striatal network, particularly the nucleus accumbens, a neural region linked to mood and anxiety disorder pathophysiology. THC may increase neuroinflammatory responses via the redox system and dysregulate inhibitory and excitatory neural balance in various brain circuits, including the striatum. Thus, interventions that can induce antioxidant effects may counteract the neurodevelopmental impacts of THC exposure. Methods: In the current study, we used an established preclinical adolescent rat model to examine the impacts of adolescent THC exposure on various behavioral, molecular, and neuronal biomarkers associated with increased mood and anxiety disorder vulnerability. Moreover, we investigated the protective properties of the antioxidant N-acetylcysteine against THC-related pathology. Results: We demonstrated that adolescent THC exposure induced long-lasting anxiety- and depressive-like phenotypes concomitant with differential neuronal and molecular abnormalities in the two subregions of the nucleus accumbens, the shell and the core. In addition, we report for the first time that N-acetylcysteine can prevent THC-induced accumbal pathophysiology and associated behavioral abnormalities. Conclusions: The preventive effects of this antioxidant intervention highlight the critical role of redox mechanisms underlying cannabinoid-induced neurodevelopmental pathology and identify a potential intervention strategy for the prevention and/or reversal of these pathophysiological sequelae.