Fatigue is increasingly recognized as a systemic manifestation of disrupted metabolic and neuroendocrine homeostasis under conditions of xenobiotic and iatrogenic stress, yet its underlying toxicological mechanisms remain poorly defined. Emerging evidence indicates that environmental toxicants and antibiotics perturb host physiology not only through direct cellular toxicity but also by destabilizing microbiota-dependent circadian regulation. In this review, we synthesize current experimental and clinical evidence to delineate a microbiota-circadian axis as a mechanistic interface linking xenobiotic exposure to systemic metabolic dysfunction and fatigue-related phenotypes. Mechanistically, toxicant- and antibiotic-induced dysbiosis disrupts the production of key microbial metabolites, including short-chain fatty acids, secondary bile acids, and tryptophan-derived compounds. These metabolites function as critical regulators of peripheral circadian clocks, mitochondrial bioenergetics, and neuroendocrine signaling. Their depletion leads to circadian misalignment, impaired metabolic efficiency, and activation of neuroinflammatory pathways, notably through a shift in tryptophan metabolism toward the kynurenine pathway and altered mesolimbic dopaminergic signaling. We further re-evaluate legacy clinical evidence on antibiotic-associated fatigue, proposing that inconsistent findings may reflect limitations in study design, including inadequate assessment of circadian disruption and delayed microbiome recovery. Importantly, circadian disruption itself emerges as a key modifier of host susceptibility, amplifying the biological impact of xenobiotic and microbial perturbations. Finally, we discuss translational implications, highlighting chronotherapeutic and microbiome-targeted strategies aimed at restoring temporal and metabolic homeostasis. By positioning fatigue as a downstream consequence of xenobiotic-driven microbiota-circadian disruption, this review provides a mechanistic framework for understanding environmentally induced systemic dysfunction and identifies potential avenues for targeted intervention.
