While Isochrysis zhanjiangensis, a marine microalga, has been widely adopted in aquaculture for its health-promoting properties, its potential as a functional food for human metabolic health remains unexplored. To bridge this gap, this study systematically evaluated the nutritional composition, biosafety, and therapeutic efficacy of I. zhanjiangensis against high-fat diet (HFD)-induced metabolic disorders in mice. Our results revealed that I. zhanjiangensis exhibits a desirable nutritional profile with no detectable toxicity, and its dietary supplementation significantly attenuated HFD-induced metabolic dysregulation. Gut microbiota profiling further demonstrated that I. zhanjiangensis supplementation restored microbial homeostasis, evidenced by mitigation of the elevated Firmicutes/Bacteroidota ratio and enrichment of beneficial genera including Muribaculum, Candidatus_Arthromitus, and Veillonella. Hepatic metabolomics identified key metabolites modulated by I. zhanjiangensis, such as N1-methyl-2-pyridone-5-carboxamide, N-acetyl-L-histidine, and eicosapentaenoic acid, which are mechanistically linked to lipid metabolism regulation. These findings not only position I. zhanjiangensis as a promising candidate for functional food development targeting HFD-induced metabolic dysregulation, but also highlight the untapped potential of aquaculture microalgae as sustainable resources for nutraceutical innovation.