Non-alcoholic fatty liver disease (NAFLD) is an increasingly prevalent ailment worldwide. Moreover, de novo lipogenesis (DNL) is considered a critical factor in the development of NAFLD; hence, its inhibition is a promising target for the prevention of fatty liver disease. There is evidence to indicate that AMP-activated protein kinase (AMPK) and sirtuin 1 (SIRT1) may play a crucial role in DNL and are the regulatory proteins in type 2 diabetes mellitus, obesity and cardiovascular disease. Therefore, AMPK and SIRT1 may be promising targets for the treatment of NAFLD. The present review article thus aimed to summarize the findings of clinical studies published during the past decade that suggested the beneficial effects of AMPK and SIRT1, using their specific activators and their combined effects on fatty liver disease. Contents1. Introduction 2. Data collection methods 3. De novo lipogenesis 4. AMPK 5. SIRT1 6. AMPK activators in NAFLD clinical studies 7. The SIRT1 activator, resveratrol, in NAFLD clinical studies 8. The combination of AMPK and SIRT1 activation 9. Conclusion