In hyperglycemia-induced complications, macrophages play important roles in disease progression, and altered digestion is a key feature that dictates macrophage function. Recent evidence indicates that kakonein (Ka) possesses anti-inflammatory activities for hyperglycemia-induced complication. In this study, we established a mouse model of Nlrp3(+/+) and Nlrp3(-/-) hyperglycemia and administering Ka, primary culture macrophages were tested by engulfing and digesting microbes. The role of macrophages in the cathepsin B-NLRP3 pathway involved in the mechanism of Ka in restoring macrophage digestion function was investigated using biochemical analyses, molecular biotechnology, and microbiology. Ka restored the function of macrophage digestion, which were same characterized by Nlrp3(-/-) mice. Meanwhile, kakonein could decrease NLRP3 inflammasome products expression and NLRP3/ASC or NLRP3/Casp1 colocalization in macrophage. Interestingly, Ka suppressed inflammasome response not by reducing NLRP3 and ASC expression but by reducing cathepsin B release and activation. And Ka restored macrophage digestion and inhibited NLRP3 inflammasome activation consistent with cathepsin B inhibitor. It is concluded that Ka reduced the release of lysosomal cathepsin B and consequently inhibited NLRP3 inflammasome activation to prevent macrophage digestion. Hence, Ka may contribute to new targets for treatment of hyperglycemia-associated dysfunction of macrophage digestion and development of innovative drugs.