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Objectives: Many attempts have focused on controlling the progression of beta-cell destruction due to diabetes apoptosis. Therefore, any treatment with the least side effects inhibiting the progression of apoptosis and the destruction of the islets of Langerhans is valuable. This survey is the first one to compare the anti-apoptotic effect of the Peganum harmala seed extract with that of harmine in rats. Materials and Methods: To this end, six equal groups (n=8) of rats (250-300 g) were selected in this experimental study. The diabetes condition was induced by the intraperitoneal administration of streptozotocin (STZ) (65 mg/kg). The methanolic extract of P. harmala seeds and harmine were gavaged to healthy and diabetic rats. The active substances of P. harmala were investigated by the highperformance liquid chromatography method. Flow cytometry was also employed to evaluate the apoptosis of beta cells. Hematoxylin and eosin and argyrophilic nucleolar organizer region staining were applied to examine pancreatic tissues. Results: The obtained results from treatment with the seed extract and harmine were similar in the treatment groups. This treatment elevated plasma insulin levels while reducing plasma glucose levels and apoptosis (P < 0.05). Finally, staining results showed that the seed extract could improve tissue damage more than harmine (P < 0.05). Conclusions: Our findings revealed that the seed extract of P. harmala is more effective in controlling diabetes and apoptosis due to diabetes compared to its active ingredient, namely, harmine. This feature seems to be due to its high percentage of antioxidants together with β-carboline compounds. [ABSTRACT FROM AUTHOR]