Background <p>Plastics are considered as the most significant global environmental concerns. Previous studies have found that microplastics can accumulate in blood and various tissues, causing reproductive, neurotoxic, and hepatotoxic effects, among others, through multiple mechanisms. The present study aims to elucidate the ameliorative role of 4-PBA against polystyrene microplastics (PSMPs)-induced nephrotoxicity.</p> Methods and results <p>A total of twenty-four female Wistar rats were randomly assigned to four experimental groups (each group, <i>n</i> = 6). The first group consisted of healthy female Wistar rats. Rats in the second group received PSMPs (10&#xa0;mg/kg) orally for five weeks. The third group received PSMPs for five weeks and 4-PBA (500&#xa0;mg/kg) orally for the last two weeks of the study. The last group was treated with PSMPs and 4-PBA (1000&#xa0;mg/kg) for five and the last two weeks, respectively. After five weeks, animals were euthanised, and kidney tissues and blood samples were collected immediately. Compared with normal control rats, animals treated with PSMPs showed a substantial rise with a percentage change in serum BUN (32.44%), creatinine (74.69%), MDA (11.62%), and nitrite (152.45%), and decreases in body weight (24.60%), kidney weight (23.96%), and GSH (64.41%). Additionally, the PSMPs group exhibited notable abnormalities in kidney histopathology. ER stress biomarkers, including GRP78 (163.23%), CHOP (363.72%), and caspase-12 (310.29%), were also found to be increased in the PSMPs group. On the other hand, 4-PBA alleviated histological abnormalities and improved biochemical indicators, as well as the expression of ER stress markers in kidney tissues.</p> Conclusion <p>The above-mentioned results suggest that 4-PBA may be a therapeutic agent against ER stress-mediated PSMPs-induced nephrotoxicity in rats.</p> Graphical abstract <p></p>