Objectives: Paracetamol (PCM) is widely used for its pain-relieving and antipyretic properties. However, acute intoxication of PCM remains one of the most common causes of drug-induced hepatic failure. A comparative study is conducted to evaluate the effectiveness of coenzyme Q10 (CoQ10) with that of liposomal CoQ10 (L-CoQ10) against PCM-induced liver injury. Method: Acute liver injury was induced by a single oral dose of PCM (1000 mg/kg). CoQ10 and L-CoQ10 treatments were given orally (10 mg/kg), 1 and 12 h following PCM intoxication. Specific oxidative stress, inflammatory and apoptotic biomarkers were measured, and then proved by histopathological examination. Results: PCM administered rats exhibited a remarkable increase in the levels of serum aminotransferase enzymes, as well as hepatic interleukin-6, C-reactive protein, malondialdehyde (MDA) and nitric oxide (NO); whereas reduced glutathione (GSH) level and superoxide dismutase (SOD) activity were decreased. BAX, Nuclear factor-kappa B (NF -KB) and cytochrome C were overexpressed, while BCL-2 was downregulated. The results of the previous parameters were supported by histopathological study of liver tissue. Using either CoQ10 or L-CoQ10 caused a significant reduction of oxidative stress by enhancing GSH and SOD activity levels and diminishing MDA and NO levels. Moreover, both CoQ10 and CoQ10 caused down regulation of pro-inflammatory cytokines and BAX, and upregulation BCL-2, and these effects mostly noticed in L-CoQ10 treated rats. Likewise, rats receiving L-CoQ10 exhibited restoration of normal hepatic architecture. Conclusion: L-CoQ10 supplement is useful for counteracting the hepatotoxicity induced by PCM overdose, via reducing the oxidative stress, inflammation and apoptosis.(c) 2022 The Authors. Published by Elsevier B.V. on behalf of King Saud University. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).