Aluminum (AL) is an important nephrotoxic agent with a high daily exposure rate and property of accumulation in tissues. This study aimed to investigate the potential protective efficacy of N-acetylcysteine (NAC) against AL exposure-induced nephrotoxicity in rats. Twenty-eight rats were randomly divided into 4 groups as control, N-acetylcysteine group (NC), AL, and AL + NC, with an equal number of rats in each group (n = 7). No application was made to the control group. A total of 150 mg/kg/day NAC was administered to the NC group and 30 mg/kg/day AL was administered to the AL group intraperitoneally (i.p.). The AL + NC group received 30 mg/kg/day AL and 150 mg/kg/day NAC i.p. Biochemical parameters in blood serum and histopathological changes in kidney tissue, oxidative stress parameters, spexin (SPX), and apoptotic protein levels were examined after 15 days. Histopathological changes, biochemical parameters, oxidative stress parameters, and apoptotic protein levels were significantly irregular in the AL group compared to the control group. Moreover, SPX levels increased in the AL group. However, NAC treatment regulated AL exposure-related changes in the AL + NC group. NAC treatment may have a prophylactic effect against nephrotoxicity due to AL exposure. SPX may play a role in AL-induced nephrotoxicity.