The present study was aimed to explore the cardio-, immuno-, and nephrotoxic effects of the antipsychotic agent clozapine (CLZ) and the alleviative potency of sulpiride (SPD) on these impairments in rats. For this purpose, 40 male rats were divided into four groups and were orally treated with saline (control), CLZ (0.5mg/kg bw), SPD (28 mg/kg bw), or a combination of CLZ and SPD (CLZ+SPD), daily for 30 consecutive days. At necropsy, blood samples and specimens from the heart, kidneys, and spleen were collected for biochemical, molecular, and histopathological investigations. The results showed that CLZ administration was associated with significantly lower immune status indices and increased serum levels of pro-inflammatory cytokines, lactate dehydrogenase, malondialdehyde, cardiac, and renal tissues injury markers. Moreover, the mRNA expression levels of Kidney Injury Molecule-1 (Kim-1), tissue inhibitor of metalloproteinase-1 (TIMP-1), and cytochrome P450 (CYP) isoforms were markedly upregulated in CLZ-treated rats, compared to the control group. On the other hand, rats treated with SPD alone showed non-significant differences in terms of immune response indices, tissue injury markers, and mRNA expression levels of Kim-1, TIMP-1, and CYP isoforms. Finally, CLZ+SPD co-treatment significantly modulated almost all biochemical indices. Besides, Kim-1, TIMP-1, and CYP2C19 mRNA expression levels were significantly downregulated, while other CYP isoforms showed no modulation, compared with CLZ-treated group. Histopathologically, CLZ-treated rats showed severe lesions in renal, splenic, and cardiac tissues, compared with control rats, which were restored in CLZ+SPD-co-treated rats. Overall, these findings demonstrate that CLZ treatment induces significant cardiac, immune, and nephropathic alterations, which were reduced with CLZ+SPD co-treatment.