Aminoglycosides as Amikacin (AMK) are widely used antibiotics however they are reported to cause considerable nephrotoxicity mediated via increased oxidative stress. The present study aimed to assess the impact of omega-3 and Saccharomyces cerevisiae (Sc) on AMK-induced nephrotoxicity in rats. Sixty Sprague Dawley rats of both sexes were assigned to ten equal groups.Group1received saline (normal control), groups 2-4 received Sc (109 CFU ml-1; p.o.), omega-3 (200 or 400 mg/kg; p.o.), respectively, group 5 received AMK (35mg/kg/day; i.p.), groups 6- 8received AMK with Sc, omega-3 (200or 400 mg/kg), respectively and groups 9-10 received AMK and Sc combined withomega-3 (200or 400 mg/kg), respectively for 4 weeks. At the end of experiments, blood samples were collected and kidneys were isolated and used for biochemical and histological studies. AMK-induced nephrotoxicity was shown by elevations in serum urea, creatinine and blood urea nitrogen parallel to decrease in serum total protein. AMK induced oxidative stress manifested by increases in kidney malondialdehyde and nitric oxide contents parallel to decreases in reduced glutathione content and superoxide dismutase activity. Besides, AMK increased kidney hydroxyproline and tumor necrosis factor-alpha contents as well as caspase-3 immunostaining. Sc, omega-3 and their combinations attenuated AMK-induced changes in kidney function tests, oxidative stress, inflammatory, apoptotic and fibrotic biomarkers. The tested agents even improved markers of kidney damage in normal animals. Histological examinations of kidney tissues confirmed the biochemical findings. Sc and omega -3 could be of therapeutic value against nephrotoxicity induced by AMK.