The aim of the present study was to investigate whether perinatal exposure to a moderate dose of delta-9-tetrahydrocannabinol (THC) alters cortical gene expression and neurotransmission, leading to enduring cognitive dysfunctions in rat offspring. To this purpose, rat dams were treated, from gestational day 15 to postnatal day 9, with THC at a daily dose (5 mg/kg, per os) devoid of overt signs of toxicity. THC did not influence reproduction parameters, whereas it caused subtle neurofunctional deficits in the adult offspring. Particularly, perinatal THC induced long-lasting alterations of cortical genes related to glutamatergic and noradrenergic systems, associated with a decrease in the cortical extracellular levels of both neurotransmitters. These alterations may account, at least in part, for the enduring cognitive impairment displayed by THC-exposed offspring. Taken together, the present results highlight how exposure to cannabinoids during early stages of brain development can lead to irreversible, subtle dysfunctions in the offspring.