Depression is linked with a high risk of type 2diabetes (T2D). The affiliation between depression and diabetes might be correlated to depression itself and, or medications recommended. Significantly, the usage of selective serotonin reuptake inhibitors (SSRIs), the most commonly antidepressants increased the hazard of developing T2D. Nevertheless, the mechanism underlying this suggestion remains vague. Omega-3 had antioxidant and anti-inflammatory activity. So, there is developing evidence that consumption of omega-3 could be expedient. The present study was carried out to investigate the potential effect of omega-3 in the fluoxetine induced alterations in the pancreas of adult male albino rats. Forty adult male albino rats were divided into four groups. Group I served as a control group. Group II received a single daily dose of 300 mg/kg of omega-3. Group III received 24 mg/kg bw/day of fluoxetine hydrochloride. Group IV received omega-3 and fluoxetine as group II and III for 30 days. Light and electron microscopic investigations were carried out. Histological examination using H & E and Masson’s Trichrome stain were carried out. The insulin expression in β cells was evaluated using immunohistochemistry. Morphometric results were subjected to statistical analysis. Investigation of group III (Fluoxetine group) showed distorted exocrine pancreas with thick interlobular septa that contained dilated congested blood vessels, cellular infiltration, and fat cells. Marked shrunken of the pancreatic islets was observed. Masson’s trichrome stain showed increased collagen fibers deposition. Electron microscopic examination revealed that most of the acinar cells had irregular shaped nuclei with peripheral heterochromatin and wide capillaries. The cytoplasm of β cells had a variety of secretory granules. Most of them had an electron dense core with increased electron lucent halo however, few β granules were empty and coalesced. Omega- 3 supplementation improved the morphology of Langerhans compared to fluoxetine group. Importantly, some pancreatic duct cells revealed a positive reaction against anti-insulin antibodies. The current results demonstrated that fluoxetine harmfully affected the histological structure of the pancreas. Omega-3 diminished effectively some histological, immunohistochemical and electron microscopic changes in a fluoxetine induced pancreatic injury. Omega-3 could stimulates β-cell regeneration from potent islet progenitor cells present in the ductal cells and these might lead to repair of the functional accomplishments of the injured pancreas to a great extent.