Background/Objectives: Cancer-related fatigue (CRF) is one of the most prevalent and disabling symptoms among patients with cancer, but its underlying mechanisms and effective management strategies have not yet been fully elucidated. Increasing evidence suggests that the microbiota-gut-brain axis (MGBA) may contribute to the pathogenesis of CRF by integrating nutritional status, intestinal barrier integrity, microbial metabolites, immune responses, and host energy metabolism. However, direct causal evidence in human CRF remains limited, and several mechanistic insights are extrapolated from other disease models. This narrative review aims to synthesize evidence for nutritional MGBA-CRF regulatory mechanisms, focusing on microbiota-associated biomarkers and microbiome-targeted dietary interventions, and to distinguish directly observed in a CRF population from indirect hypothetical mechanisms. Methods: This review synthesizes current evidence on the nutritional regulatory mechanisms linking the MGBA to CRF, with particular attention to microbiota-associated biomarkers and dietary or microbiome-targeted interventions. Results: Microbiota dysbiosis, reduced production of short-chain fatty acids, disrupted tryptophan metabolism, and increased intestinal permeability may lead to systemic inflammation, neuroendocrine dysfunction, and impaired mitochondrial function, thereby exacerbating fatigue. Moreover, nutritional factors, dietary patterns, and microbiota-targeted interventions may help restore microbiota homeostasis and alleviate fatigue-related biological dysregulation. Conclusions: A deeper understanding of MGBA may help in developing personalized nutritional strategies for patients with cancer experiencing fatigue symptoms and support more effective management of CRF.
