Given the importance of (−)-epigallocatechin gallate (EGCG) as an autophagy-enhancing and thereby lipid-lowering agent, optimization of its activity warrants its therapeutic potential in the treatment of hepatic diseases as well as metabolic disorders. On the basis of our previous observations that structural modifications provided substantial improvements in the bioactivity of EGCG, we investigated the autophagy-enhancing activity of EGCG derivatives. Among 14 EGCG derivatives, E10 with a phenylalanine attached to the D ring of EGCG exhibited the most promising effects in stimulating autophagy in Huh7 cells, which was supported by several lines of evidence: (1) stimulation of autophagy revealed by an increased amount of LC3B-II (4.1 ± 0.8-fold compared to the control) as well as the 2.0 ± 0.1-fold activation of adenosine monophosphate-activated protein kinase in the presence of E10 and (2) E10-stimulated autophagic flux demonstrated by a 1.6 ± 0.4-fold increase in LC3B-II upon co-treatment with chloroquine, 38.1 ± 5.6% reduction of p62/SQSTM1, and an increase in the formation of autophagic compartments visualized by both CYTO-ID staining (3.0 ± 0.1-fold) and tandem RFP–GFP–LC3 fluorescence (2.7 ± 0.4- and 3.2 ± 0.3-fold for green and red fluorescence, respectively). Finally, the autophagy-inducing activity of E10 culminated in a 5.3-fold reduction of hepatic lipid accumulation caused by fatty acids. In all of the assay settings, E10 was consistently 1.3–3.5-fold more potent than EGCG. Taken together, we demonstrated a significant increase in autophagy-stimulating activity of EGCG through structural modifications.