Acute liver failure (ALF) is a clinical condition with an unclear history of pathophysiology, Punica granatum L peel and Pistacia atlantica leaves are differentiated by the presence of a wide range of flavonoids and phenolic as antioxidant compounds. The purpose of this study was to investigate the hepatoprotective effects of Punica granatum L. peel and Pistacia atlantica leaves either in their normal and/or in their nano forms against thioacetamide induced acute liver failure in a rodent model. Male Wistar rats (n=60) were divided into six equal groups, the first group employed as a control; The second group administered a dose of 350 mg /Kg/ b.w of thioacetamide (TAA)-ip, from the third to the sixth group received TAA + [2mls / 100 g b.w/d] of aqueous extracts of Punica granatum L and Pistacia atlantica either in their normal and/or Nano forms consecutively for (14 days) .In the TAA challenged group, there was a substantial increase in liver enzymes, lipid profiles, LPO ( p= 0.05), and NO, as well as a substantial drop in GSH and SOD, which was followed by an increase in inflammatory cytokine (IL6, TNF-, and AFP), as well as a considerable increase in HSP70 level and DNA degradation. However, ip nano treatment of both extracts resulted in considerable and subsequent improvement of most of the compromised indicators. In conclusion: The current findings demonstrated the great performance of both plant nano extracts, as well as their hepatoprotective effects and possible therapeutic usefulness in the treatment of TAA-induced acute liver failure in experimental animals.