Background: Tramadol is nephrotoxic in over doses N-acetylcysteine is effective against inflammatory processes and oxidative stress. Objective: Study of tramadol- induced nephrotoxicity on the rats and assess the possible protection of N-acetylcysteine. Material and Methods: Forty adult albino rats were obtained from the breading animal house of Faculty of Pharmacy, Al-Azhar University. The rats were housed in the animal house at Faculty of Pharmacy, Al-Azhar University under the suitable and standard conditions of temperature and feeding from January, 2021 till February, 2021. The rats were divided  into four groups Group I (control group): the rats of this group was given 30 ml /kg saline daily for thirty days orally; group II (treated with tramadol): the rats of this group were given l5.5 mg /kg tramadol orally daily for thirty days; Group III (Toxic dose tramadol): The rats of this group were given 30 mg /kg tramadol orally daily for thirty days; Group IV (treated with toxic dose of tramadol and N-acetyl cysteine): The rats of this group were given 30 mg /kg tramadol and N-acetylcysteine 100 mg/kg orally daily for thirty days. The rats at the last day of the experiment were killed and their kidneys were collected for histological evaluation using hematoxylin and eosin and Masson trichrome, and examined under light and transmission electron microscope. Also, Blood samples were taken for measurement of urea and creatinine. The data obtained from biochemical results for all groups were expressed as means and subjected to statistical analysis. Results: Treatment of rats with toxic dose of tramadol (group III) showed marked damage in the renal tissues, The damage in the renal tissues was improved in rats that were given N- acetylcysteine together with tramadol (group IV). However, tramadol that was given in a therapeutic dose (Group II) did not cause any damage in the kidney. Conclusion: N-acetylcysteine partially improves the tramadol –induced nephrotoxicity.