Background: Orlistat is one of the common medicines in treating overweight, and its use may cause several side effects. Curcumin, a yellow phenolic compound isolated from Curcuma longa's rhizome, possesses several pharmaceutical effects due to its antioxidant and anti-inflammatory properties. Aim: This work aimed to test the possible protective effect of curcumin against orlistat-induced hepatorenal and cerebellar toxicities in obese albino rats. Material and Methods: Forty adult male albino rats were equally separated into four groups; Group I: the control group. Group II: curcumin group; Group III: orlistat group. Group IV, rats were given orlistat (32mg/kg/day) then curcumin (200mg/kg body weight three times per week for six weeks). Results: In the liver of rats treated with orlistat, the hepatic cells appeared with degenerated cytoplasm containing many vacuoles and darkly stained nuclei. Similarly, some glomeruli in the kidney were atrophic or fractured, the cerebellar cortex is spongiosis, and the Purkinje cells, granule, and molecular cells were degenerated. When rats were treated with orlistat and curcumin, the liver, kidney, and cerebellar the histopathological changes were relatively recovered to the control ones. The number of Kupffer cells, glomerular diameter, Bowman's space width, and the dimensions of the renal tubules significantly decreased, and the epithelial height retrains normal as compared to orlistat treated rats. The levels of MDA, dopamine, and glutamate significantly decreased, and the activity of SOD significantly increased. The rising in PCNA and Bcl2 expression after orlistat is significantly decreased in the studied organs after curcumin treatment. Conclusion: This study concluded that curcumin may have a potential role in improving hepatorenal and cerebellar toxicities after orlistat treatment.