Apigenin, as a natural flavonoid, has been proved to have many biological effects. Our previous research has found the antiadipogenic effects of apigenin on HepG2 cells. Autophagy is intimately associated with the metabolism of lipid droplets (LDs) and is considered to be one of the lipid breakdown pathways. However, there is no study to elucidate the lipid-lowering mechanism of apigenin from the perspective of autophagy. Here, we investigated the possible role of apigenin in autophagy and lipid accumulation in palmitic acid (PA)-induced HepG2 cells. Our results showed that apigenin increased autophagosome formation and the LC3-II/I ratio, but decreased the p-mTOR/mTOR ratio and P62 protein expression. The effects of apigenin were blocked by chloroquine (CQ). Likewise, apigenin significantly stimulated autophagic flux in the cytoplasm. This effect also could be blocked by CQ. Moreover, apigenin decreased the lipid content and co-localization of LDs with LC3, and CQ could block these effects. Thus, we proposed that apigenin induced autophagy and stimulated autophagic lipid degradation in PA-treated HepG2 cells.