ABSTRACT: Undaria pinnatifida fucoidan (UPF), a bioactive sulphated polysaccharide, has been widely recognised for its anti-inflammatory, antioxidant, antitumor, anticoagulant, antiviral, and immunomodulatory properties. However, the precise mechanisms through which UPF regulates systemic inflammation, oxidative stress, and neuronal health remain unclear. This study aimed to investigate the effects of UPF supplementation on systemic inflammation, gut microbiota composition, and neuronal protein expression in a murine model. A total of 64 C57BL/6J mice were administered UPF (400 mg/kg/day) for 10 weeks, and its impact on key inflammatory markers, gut microbiota, and neuronal proteins was assessed. UPF significantly downregulated pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) in skeletal muscle, small intestine, and hypothalamus, while also reducing circulating IL-1α levels. Moreover, UPF altered gut microbiota composition by decreasing the abundance of the inflammatory bacterial marker Enterobacteriales order. In the brain, proteomic analysis of the nucleus accumbens revealed that UPF modulated the expression of proteins involved in immune response, neuronal stability, oxidative and endoplasmic reticulum stress, neurotransmitter regulation, and neuroinflammation. These findings suggest that UPF supplementation effectively mitigates systemic inflammation, supports muscle and gut health, and enhances neuronal function, highlighting its potential as a therapeutic intervention for inflammation-related disorders and neurodegenerative diseases.