This review summarizes the current understanding of the pathogenesis and progression of metabolic dysfunction-associated steatotic liver disease (MASLD)-driven hepatocellular carcinoma (HCC), and discusses the potential of bioactive compounds in its treatment. MASLD has become the leading cause of HCC, with a projected 45%–130% increase in annual cases by 2030. The exact molecular mechanisms underlying MASLD-driven HCC remain unclear, necessitating further research. Emerging studies highlight the potential of bioactive compounds to prevent the progression of MASLD to HCC through anti-inflammatory, lipid metabolic, and gut microbiota pathways. The review discusses the application of these compounds in mitigating MASLD-driven HCC, categorizing drugs based on their mechanisms of action. Key factors contributing to MASLD-driven HCC include chronic inflammation, oxidative stress, gut microbiome dysbiosis, lipotoxicity, and glucotoxicity. Anti-inflammatory drugs such as saroglitazar, tipifarnib, and liraglutide have shown promise in reducing HCC progression. Antioxidant drugs like lycopene and curcumin also exhibit potential in inhibiting MASLD-driven HCC. Anti-fibrotic drugs such as pioglitazone and ezetimibe have been shown to reduce hepatic tumorigenesis. Drugs regulating lipid metabolism, such as n-3 PUFAs and dietary mulberry leaf powder, also show potential. Regulating gut microbiota, such as through daikenchuto and curcuma, may help in preventing MASLD-driven HCC. Additionally, modulating immunity, such as through metformin and losartan, may offer therapeutic benefits. The review highlights the importance of understanding the molecular mechanisms of MASLD-driven HCC and the potential of pharmacological modulation as a novel therapeutic approach. Despite progress, further research is needed to explore effective treatments for MASLD-driven HCC.This review summarizes the current understanding of the pathogenesis and progression of metabolic dysfunction-associated steatotic liver disease (MASLD)-driven hepatocellular carcinoma (HCC), and discusses the potential of bioactive compounds in its treatment. MASLD has become the leading cause of HCC, with a projected 45%–130% increase in annual cases by 2030. The exact molecular mechanisms underlying MASLD-driven HCC remain unclear, necessitating further research. Emerging studies highlight the potential of bioactive compounds to prevent the progression of MASLD to HCC through anti-inflammatory, lipid metabolic, and gut microbiota pathways. The review discusses the application of these compounds in mitigating MASLD-driven HCC, categorizing drugs based on their mechanisms of action. Key factors contributing to MASLD-driven HCC include chronic inflammation, oxidative stress, gut microbiome dysbiosis, lipotoxicity, and glucotoxicity. Anti-inflammatory drugs such as saroglitazar, tipifarnib, and liraglutide have shown promise in reducing HCC progression. Antioxidant drugs like lycopene and curcumin also exhibit potential in inhibiting MASLD-driven HCC. Anti-fibrotic drugs such as pioglitazone and ezetimibe have been shown to reduce hepatic tumorigenesis. Drugs regulating lipid metabolism, such as n-3 PUFAs and dietary mulberry leaf powder, also show potential. Regulating gut microbiota, such as through daikenchuto and curcuma, may help in preventing MASLD-driven HCC. Additionally, modulating immunity, such as through metformin and losartan, may offer therapeutic benefits. The review highlights the importance of understanding the molecular mechanisms of MASLD-driven HCC and the potential of pharmacological modulation as a novel therapeutic approach. Despite progress, further research is needed to explore effective treatments for MASLD-driven HCC.