Dysbiosis of the gut microbiota may lead to a wide range of metabolic, neurological, intestinal and cardiovascular disorders and even to tumorigenesis. Evidence suggests that the gut-brain axis (GBA) plays a crucial role in the treatment of these diseases. Many plant-derived natural actives modulate the gut microbiota and its metabolites, gut hormones and neurotransmitters through a variety of mechanisms, and these actions contribute to the alleviation of irritable bowel syndrome, type 2 diabetes mellitus, cancer, and brain disorders. This review focuses on how natural products act through the GBA to protect the central nervous system, regulate metabolism and promote apoptosis in cancer cells. The role of gut microbiota metabolites and neurotransmitter release in modulating inflammation-related factors, promoting or reducing oxidative stress, and activating or inhibiting related signaling pathways is also discussed. This comprehensive overview of the complex GBA mechanisms deepens the understanding of how natural products can target the GBA to treat disease, providing valuable insights into the development and utilization of these natural interventions.