Autophagy is a highly conserved catabolic process observed in all eukaryotic cells to maintain homeostasis. For cancer, the role autophagy play is complex and is tumor- and context-dependent regarding microenvironment. With advanced research into autophagy physiologically and pathologically, targeting autophagy is becoming a novel strategy for cancer therapy. Natural compounds are a treasure trove for potential new drugs and an increasing number of natural compounds are reported to exhibit autophagy modulating effects. In this study, we reported two natural compounds that regulate autophagy negatively or positively, respectively, in different context of cancer therapy. In the first study, we interpreted the dose-response relationship of Berberine (BBR) on human breast cancer cells treated with chemotherapeutic agents and found though high-dose BBR (HDB) enhanced the anti-cancer effect of chemotherapeutic agents, low-dose BBR (LDB) (0.31, 0.62, 1.25 μM) antagonized them on the contrary. The potential mechanisms of this were analyzed as follows: (1) Stimulated oxidative stress to induce autophagy through 5’-adenosine monophosphate-activated protein kinase (AMPK)-serine/threonine kinase 1 (ULK1)-Beclin1 pathway; (2) Enhanced antioxidant enzymes including HO-1 and SOD by activating Nrf2 pathway. In the second study, we elucidated the dose-response curve of another natural compound, Momordin Ic (MIc), on human epidermal growth factor receptor (EGFR)-mutant lung cancer cells. Our results showed that MIc is a potential anti-lung cancer agent. The potential mechanisms were studied as follows: (1) Induced ROS generation and mitochondrial damage; (2) Inhibited autophagy by neutralizing lysosomal acidity and impairing lipid raft-related lysosomal efficacy. Additionally, MIc showed promising effects on sensitizing human EGFR-mutant lung cancer cells to EGFR tyrosine kinase inhibitors (TKIs). In summary, these studies identified a natural autophagy inducer and a natural autophagy inhibitor, and their potential in anti-cancer therapy were also discussed. BBR, as a promising anti-cancer natural product, induced protective autophagy at low dose and therefore contributed to chemotherapy resistance, which should be noted in the clinical use. On the other hand, MIc, as a novel autophagy inhibitor, showed significant effect on lung cancer cells either alone or with EGFR TKI, which should be further studied for more surprising findings.