<p>T his article is aimed at assessing the anti-fibrotic action of plant-based fabricated cerium oxide nanoparticles (CeO₂NPs). The <i>Carissa carandas</i> aerial parts methanolic extract was utilized to prepare CeO₂NPs, where the dispersal of particle size distribution and zeta potential value was 61.9 nm and − 18.94 mV, respectively, verifying the successful synthesis of CeO₂NPs. In rats, CeO₂NPs were intravenously injected at doses of 0.1 and 0.5 mg/kg twice a week for a month, in parallel with thioacetamide (TAA, 200 mg/kg, i.p). Our findings revealed that CeO₂NPs alleviated the alteration in serum GPT, GOT, ALP, total bilirubin, albumin, and total protein levels induced by TAA. Additionally, the hepatic oxidative insult due to TAA was inferred by elevation in malondialdehyde and reduction of glutathione content, which in combination with downregulation of SIRT1, Nrf2, and HO-1 in hepatic tissues was improved by CeO₂NPs. A clear repression in hepatic fibrosis was observed in CeO₂NP-treated groups as demonstrated by significant downregulation in TGF-β1 and p-Smad 2 and 3 proteins and COL1A1, MMP-2, and α-SMA expressions in hepatic tissues. The histopathological outcomes exhibited a considerable accumulation of collagen fibers in hepatocytes in TAA-challenged rats, which was ameliorated by CeO₂NPs. Also, CeO₂NPs dampened the death of hepatic cells via blocking caspase 3 activation as indicated by the immunohistochemical results. The in silico investigations documented the powerful binding affinities of TGF-β1, COL1A1, MMP-2, p-Smad2, p-Smad3, SIRT1, Nrf2, and HO-1 proteins with CeO₂NPs. In conclusion, this study emphasized the efficacy of CeO₂NPs as a potent anti-fibrotic agent through upregulating SIRT1/Nrf2/HO-1 and downregulating TGF-β1/Smads pathways.</p>