Overnutrition triggers obesity and metabolic dysregulation, causing metaflammation. D-allulose, exhibits anti-obesity and hypoglycemic benefits. However, its involvement in metaflammation remains incompletely understood. In this study, high-fat diet-fed mice were supplemented with 300 mg/kg of D-allulose for 60 days. Levels of inflammation in various tissues, changes in intestinal barrier function, and gut microbiota composition, which serve as key markers of metaflammation, were analyzed. We foud that D-allulose significantly attenuated HFD-induced metaflammation, evidenced by a reduction in inflammation levels and in the activation of proinflammatory macrophages in adipose tissue. Additionally, D-allulose effectively restored impaired intestinal barrier function in HFD-fed mice by enhancing the expression of tight junction proteins, replenishing goblet cell populations, and modulating intestinal flora composition, which improved intestinal barrier integrity and contributed to the attenuation of metaflammation. Our findings highlight the potential of D-allulose in obesity and metaflammation management and provide new directions for future applications and advancements of D-allulose.