Purpose <p>This review aims to comprehensively elucidate the pharmacological profile of Andrographolide, Curcumin and Piperine, emphasizing their receptor-binding mechanisms, molecular targets and synergistic interactions involved in oxidative stress modulation, inflammatory control and hepatoprotective activity.</p> Objective <p>The objective of this review is to critically evaluate the hepatoprotective potential and enhanced pharmacological efficacy of Andrographolide, Curcumin and Piperine, independently and in combination, with special reference to their molecular mechanisms of action contributing to liver protection and tissue regeneration.</p> Methods <p>A systematic and extensive literature survey was conducted using scientific databases including ScienceDirect, Scopus, PubMed, Web of Science, Hinari and Google Scholar. Relevant studies were selected to extract data on pharmacodynamics, receptor-binding mechanisms, molecular pathways and synergistic interactions among the bioactives.</p> Results <p>Andrographolide exhibits potent anti-inflammatory effects through inhibition of nuclear factor-kappa B (NF-κB) activation via suppression of inhibitor kappa B alpha (IκBα) phosphorylation, thereby reducing pro-inflammatory cytokines (TNF-KBα, IL-1β, IL-6) and enhancing anti-inflammatory IL-10 expression. It also downregulates mitogen-activated protein kinase (MAPK) signaling cascades (ERK1/2, JNK, p38 MAPK) and inhibits COX-2 and iNOS expression, reducing prostaglandin and nitric oxide synthesis. Curcumin exerts hepatoprotective and antioxidant effects through modulation of Nrf2, NF-κB, TGF-β1, PI3K/Akt and AMPK pathways, while Piperine enhances bioavailability and potentiates the pharmacological actions of both.</p> Conclusion <p>The review highlights the complementary and synergistic hepatoprotective mechanisms of Andrographolide, Curcumin and Piperine, suggesting that their combined use may offer a promising, multi-targeted approach for liver disease management and future therapeutic development.</p> Lay Summary <p> Liver diseases pose a major global health concern, driving the search for safe and effective therapeutic alternatives. Natural phytochemicals such as andrographolide (<i>Andrographis paniculata</i>), curcumin (turmeric) and piperine (black pepper) have demonstrated significant hepatoprotective and regenerative potential. These compounds exert antioxidant, anti-inflammatory and anti-fibrotic effects by modulating key molecular pathways involved in oxidative stress and inflammation. Piperine enhances the bioavailability and pharmacological efficacy of curcumin, resulting in improved therapeutic outcomes. In combination, these bioactives exhibit synergistic effects that protect hepatocytes, attenuate cellular damage and promote tissue regeneration. Their integrated action supports detoxification, metabolic balance and recovery of liver function following chronic injury. Emerging evidence suggests that such phytochemical-based interventions could serve as promising adjuncts or alternatives to conventional hepatoprotective therapies. Further research and clinical validation are essential to confirm their long-term safety, efficacy and translational potential in promoting hepatic repair and overall liver health.</p> Graphical Abstract <p></p>