There has been a growing global interest in the potential health benefits of edible natural bioactive products in recent years. Ganoderma lucidum, a medicinal mushroom, has gained attention for its decadent array of therapeutic and pharmaceutical compounds. Notably, G. lucidum exhibits significant anti-cancer effects against various cancer types. Polysaccharides, a prominent component in G. lucidum, are pivotal in conferring its diverse biological and medicinal properties. The primary focus of this study was to investigate the anti-cancer activities of G. lucidum polysaccharides (GLPs), with particular attention to their potential to mitigate chemotherapy-associated toxicity and enhance targeted drug delivery. Our findings reveal that GLPs exhibit anti-cancer effects through diverse mechanisms, including cytotoxicity, antioxidative properties, apoptosis induction, reactive oxygen species (ROS) generation, and anti-proliferative effects. Furthermore, the potential of GLPs-based nanoparticles (NPs) as delivery vehicles for bioactive constituents was explored. These GLPs-based NPs are designed to target various cancer tissues, enhancing the biological activity of encapsulated compounds. As such, GLPs derived from G. lucidum represent a promising avenue for inhibiting cancer progression, minimizing chemotherapy-related side effects, and supporting their utilization in combination therapies as natural adjuncts.