Scope Gut barrier dysfunction and inflammation originating from a dysbiotic gut microbiota (GM) are strongly associated with a high‐fat diet (HFD). Anthocyanins from Lycium ruthenicum (ACs) show antiobesity effects through modulating the GM. However, the mechanism linking the antiobesity effects of ACs and GM modulation remains obscure. Methods and results To investigate the ameliorative effects of ACs on colonic barrier dysfunction and inflammation, mice are fed an HFD with or without ACs at doses of 50, 100, and 200 mg kg−1 for 12 weeks. AC supplementation reduced weight gain, enriched short‐chain fatty acid (SCFA)‐producing bacteria (e.g., Ruminococcaceae, Muribaculaceae, Akkermansia, Ruminococcaceae_UCG‐014, and Bacteroides) and SCFA content, depleted endotoxin‐producing bacteria (e.g., Helicobacter and Desulfovibrionaceae), and decreased endotoxin (i.e., lipopolysaccharide) levels. SCFAs substantially activated G protein‐coupled receptors (GPRs), inhibited histone deacetylases (HDAC), increased intestinal tight junction mRNA and protein expression levels, reduced intestinal permeability, and protected intestinal barrier integrity in HFD‐induced mice. These effects mitigate intestinal inflammation by inhibiting the LPS/NF‐κB/TLR4 pathway. Conclusion These data indicates that ACs can mitigate colonic barrier dysfunction and inflammation, induce SCFA production and inhibit endotoxin production by modulating the GM in HFD‐fed mice. This finding provides a clue for understanding the antiobesity effects of ACs. Lycium ruthenicum anthocyanins reduce weight gain; improve HFD‐induced gut microbiota dysbiosis; significantly enrich short‐chain fatty acid (SCFA)‐producing bacteria, SCFA content, and SCFA receptor expression; and decrease endotoxin‐producing bacteria and endotoxin levels in the gut of high‐fat diet‐induced mice. Increasing SCFAs and reducing endotoxins inhibit LPS/TLR4/NF‐κB activation and increase colonic barrier function at the mRNA and protein levels after AC administration.