Chemotherapy-induced cognitive impairment (CICI), often referred to as "chemobrain," is a frequently persistent complication that significantly affects memory, attention, executive function, and overall quality of life among cancer survivors. Although mitochondrial dysfunction, oxidative stress, neuroinflammation, and gut microbiota dysbiosis have each been implicated in its pathogenesis, the way these processes interact to drive cognitive decline remains incompletely understood. In this narrative review, we explore the current evidence supporting mitochondrial reprogramming as a central mechanistic link connecting chemotherapy-induced alterations in the gut-brain axis to neuronal dysfunction. Here, mitochondrial reprogramming encompasses not only overt mitochondrial damage but also adaptive and maladaptive alterations in mitochondrial bioenergetics, biogenesis, mitophagy, and metabolic signaling in response to chemotherapeutic stress. We discuss how oxidative stress, impaired mitochondrial quality control, and key inflammatory and stress-response pathways, including Nrf2/Keap1, NF-κB, the AMPK-SIRT1-PGC-1α axis, and mtDNA-mediated cGAS-STING signaling, may converge to promote neuronal injury and cognitive impairment. We further examine the contribution of chemotherapy-induced gut dysbiosis and microbiota-derived metabolites, such as short-chain fatty acids (SCFAs) and lipopolysaccharide (LPS), in modulating mitochondrial function, neuroinflammation, and blood-brain barrier (BBB) integrity via the gut-brain axis. Importantly, we differentiate findings derived directly from CICI models from those extrapolated from related fields such as neurodegenerative disorders, aging, and microbiome research, while highlighting current knowledge gaps and the scarcity of clinical data. Finally, we discuss promising therapeutic strategies aimed at restoring mitochondrial homeostasis and modulating the gut microbiota and outline priority areas for future research to facilitate the translation of these mechanistic insights into effective clinical interventions for cancer survivors.
