This study sought to evaluate the role of N-acetyl cysteine (NAC) on ibuprofen-induced hepatotoxicity in rats. The rats were divided into six groups. Group 1 (control group) received carboxy-methyl cellulose. Group 2 (untreated group) was given ibuprofen. Group 3 administrated with ibuprofen and silymarin. Groups 4, 5, and 6 were given ibuprofen and NAC. We assessed histopathological examinations and serum biochemical parameters such as alkaline phosphatase (ALP), glutamate pyruvate transaminase (GPT), urea, glutamate oxaloacetate transaminase (GOT), uric acid, lipid profile, serum interleukin-1 beta (IL-1β), catalase (CAT), superoxide dismutase (SOD), vitamin C (Vit C), protein carbonyl (PC), and ferric reducing antioxidant power (FRAP). Group 2 revealed a remarkable elevation (p < 0.05) in serum ALP, GPT, GOT, lipid profile (except HDL-C), PC, uric acid, MDA, serum IL-1β, and its hepatic gene expressions relate to group 1. Also in group 2, plasma FRAP and liver CAT, SOD, and Vit C significantly reduced (p < 0.05) as opposed to group 1. Nevertheless, NAC and silymarin led to improvement in the above parameters in contrast with those of group 2 in the treated rats. Our results confirmed protective effects of NAC on ibuprofen-induced hepatoxicity in male rats through increasing parameters such as CAT, SOD, Vit C, and FRAP. © 2022, The Author(s), under exclusive licence to Springer-Verlag London Ltd., part of Springer Nature.