Background: Although the beneficial role of adipose-derived mesenchymal stem cells (ADMSCs) in acute liver injury has been addressed by numerous studies employing different liver injury inducers, the role of rat AD-MSCs (rAD-MSCs) in diclofenac sodium (DIC) - induced acute liver injury has not yet been clarified. Objective: This study aimed to investigate whether rat adipose- rAD-MSCs injected intraperitoneal could restore the DIC-induced hepatoxicity. Methods: Hepatotoxicity was induced by DIC in a dose-based manner, after which intraperitoneal injection of rAD-MSCs was performed. Results: Here, the transplanted cells migrated to the injured liver, and this was evidenced by detecting the specific SRY in the liver samples. After administering DIC, a significant decrease in body weight, survival rate, serum proteins, antioxidants, anti-apoptotic gene expression, and certain growth factors, whereas hepatic-specific markers, pro-inflammatory mediators, and oxidative, pro-apoptotic, and ER-stress markers were elevated. These adverse effects were significantly recovered after engraftment with rAD-MSCs. This was evidenced by enhanced survival and body weight, improved globulin and albumin values, increased expression of SOD, GPx, BCL-2, VEGF, and FGF-basic expression, and decreased serum ALT, AST, ALP, and total bilirubin. rAD-MSCs also reduced liver cell damage by suppressing the expression of MDA, IL1B, IL-6, BAX, JNK, GRP78/BiP, CHOP, XBP-1, and cleaved caspase 3/7. Degenerative hepatic changes and multifocal areas of fatty change within liver cells were observed in DICreceived groups. These changes were improved with the transplantation of rAD-MSCs. Conclusions: We could conclude that targeted AD-MSCs could be applied to reduce hepatic toxicity caused by NSAIDs (DIC)