The beneficial effects of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) on nonalcoholic fatty liver disease (NAFLD) have been well documented; however, the underlying mechanism was not known. In a new study, 1,25(OH)2D3 is shown to protect against hepatic steatosis by inducing autophagy — a protective pathway that maintains intracellular homeostasis in response to different stressors. Feeding mice a high-fat diet (HFD) for 4 weeks induced hepatic steatosis; however, liver damage was attenuated in HFD-fed mice injected with 1,25(OH)2D3. Autophagic flux and expression of markers of autophagy were increased in HFD-fed mice treated with 1,25(OH)2D3; moreover, inhibition of autophagy by 3-methyladenine abrogated the protective effects of 1,25(OH)2D3 against HFD-induced hepatic steatosis. 1,25(OH)2D3 also reduced inflammation and regulated lipid metabolism in HFD-induced fatty livers. The findings highlight the potential of using 1,25(OH)2D3 and of inducing autophagy to treat NAFLD.