In order to explore the regulatory effects of crab meat protein (CMP) on systemic low-grade inflammation in mice and its correlation with gut microbiota and short-chain fatty acids (SCFAs), in this study, mice were randomly divided into a blank (control) group, a model group, a fish oil group, and low-, medium-, and high-dose CMP groups. After 7 days of intervention, serum levels of IL-6, IL-2, IL-1β, TNF-α, lipopolysaccharide (LPS), fecal SCFA concentrations, and the composition of gut microbiota were determined. The results showed that compared with the blank group, the model group’s serum LPS, IL-6, IL-2, IL-1β, and TNF-α levels were significantly elevated by 220.52%, 79.21%, 28.51%, 114.30%, and 111.92%, respectively, and their relative abundances of Lachnospiraceae_NK4A136_group, Bacteroides, and Lactobacillus, and fecal butyric acid, valeric acid, and isobutyric acid contents were significantly reduced by 73.99%, 54.02%, 68.31%, 59.51%, 30.49% and 7.49%, respectively. CMP administration restored serum inflammatory factors, gut microbiota diversity and richness to the levels almost the same as those of the blank group, while increasing significantly the relative abundance of SCFA-producing bacteria and the contents of fecal butyric acid, valeric acid, and isobutyric acid. The intervention of the CMP outcome was better than that of IM. According to correlation analysis, butyric acid and valeric acid were negatively correlated with IL-2, whilst isobutyric acid was negatively correlated with IL-1β. Furthermore, Lachnospiraceae_NK4A136_group showed positive correlations with valeric acid and butyric acid, Bacteroides exhibited a positive correlation with butyric acid, and Lactobacillus displayed a positive correlation with isobutyric acid. In conclusion, CMP can alleviate systemic low-grade inflammation induced by capsaicin, and this alleviation is associated with the gut microbiota and its metabolites butyric acid, isobutyric acid, and valeric acid.