<p>Piperazine ferulate (PF) is a compound synthesized from the reaction between ferulic acid and piperazine hexahydrate. PF has demonstrated various antioxidative and anti-inflammatory properties, indicating its potential as a protective agent. Cisplatin (Cis) is a widely used anticancer agent; however, it has been associated with various organ toxicities, including hepatotoxicity. Cis-induced hepatotoxicity has been studied previously; however, the full toxicological mechanisms remain inadequately understood. The current research aimed to examine the protective impact of PF against hepatocellular insult induced by Cis and to elucidate the underlying mechanisms involved. The impact of PF (50 mg/kg, orally for 21 consecutive days) on the hepatic injury induced by a single dose of Cis (7.5 mg/kg intraperitoneally) was assessed in a rat model. Serum liver function parameters, oxidative stress, and inflammatory biomarkers were evaluated in hepatic tissue samples. Histopathological and immunohistochemical alterations in the hepatic tissue were studied. The molecular mechanisms by which PF alleviates hepatic toxicity were investigated through Western blotting and PCR analysis. PF reduced changes in body weight, enhanced liver function by ameliorating histopathological alterations and mitigating hepatocellular function and toxicological parameters in serum and tissue, and demonstrated antioxidant, anti-inflammatory, and anti-fibrotic properties, as indicated by the findings. Per the PCR results, PF enhanced the expression of Keap-1 and Nrf-2. Additionally, Western blotting results showed that PF reduced the protein expression levels of HO-1 and NQO-1. The current study underscored the potential of PF in mitigating liver damage in a rat model of Cis-induced hepatotoxicity, although additional clinical research is warranted.</p> Graphical Abstract <p></p>