Natural compounds including alkaloids, flavonoids, terpenoids, and polyphenols demonstrate ability to modulate the PI3K/Akt/mTOR pathway, which controls autophagy—the cellular recycling process often hijacked by cancer cells for survival. These plant-derived molecules effectively alter autophagic flux to suppress tumor proliferation and enhance programmed cell death across multiple cancer models. The mechanistic targeting represents a sophisticated approach to cancer therapy, as the PI3K/Akt/mTOR pathway serves as a master regulator of cell growth, metabolism, and survival. What makes this particularly compelling is the emerging evidence for synergistic combinations with conventional treatments—natural products appear to enhance chemotherapy efficacy while reducing toxicity and overcoming drug resistance. This positions botanical compounds not as alternative medicine but as precision adjuvants to standard care. However, the translational gap remains substantial. Poor pharmacokinetic properties plague most natural products, limiting bioavailability and clinical utility. While the mechanistic rationale is sound and preclinical data promising, the pharmaceutical industry's historical struggle with natural product optimization suggests these findings represent early-stage discoveries rather than near-term therapeutic breakthroughs.