Background <p>Although fatigue is one of the most prevalent symptoms in patients with multiple sclerosis (MS), its underlying mechanisms remain insufficiently understood. Emerging evidence suggests that interoceptive sensibility and maladaptive metacognitive beliefs may play a central role in the development and maintenance of fatigue. The present study examined the interplay between interoceptive sensibility, maladaptive metacognitive beliefs, affective symptoms, and fatigue in individuals with MS.</p> Methods <p>In this cross-sectional study, 240 patients with relapsing–remitting MS completed validated self-report measures of interoceptive sensibility, metacognitive beliefs, fatigue, and affective symptoms. Symptom networks were estimated using EBICglasso regularization. Expected influence and bridge expected influence indices were calculated to identify central and bridging nodes, with network stability tested via non-parametric bootstrapping. Based on network results, serial mediation analyses were conducted to examine pathways linking interoceptive sensibility, metacognition, anxiety, and fatigue.</p> Results <p>In the network analysis, anxiety and general fatigue emerged as primary bridging symptoms, while the Multidimensional Assessment of Interoceptive Awareness subscale “Not Worrying” showed negative bridge values, suggesting potential protective effects. Cognitive confidence also displayed significant bridge connections with fatigue and affective symptoms. Mediation analyses demonstrated that the protective effect of Not Worrying on general fatigue was indirectly effected by reduced anxiety and increased cognitive confidence (total indirect effect: b = − 0.92, 95% CI [–1.24, − 0.61]).</p> Conclusion <p>Fatigue is a complex structure intertwined with interoceptive sensibility, metacognitive beliefs, and psychological symptoms. Approaches such as metacognitive therapy and mindfulness-based interventions may therefore be particularly effective in alleviating MS fatigue.</p>