Diabetic kidney injury is an almost unavoidable complication in diabetic patients. The activation of macrophages with high glucose in the patient's body is a key factor in triggering diabetic kidney disease (DKD). Mogrosides are commonly used sweeteners, but their effects on diabetic kidney injury are still unclear. This study used THP-1 cell models and diabetic mouse models to examine the impacts and pathways of mogrosides in inhibiting hyperglycemia-activated macrophages and alleviating kidney damage. This study used high glucose (33.3 mmol/L) to induce activation of macrophage-like THP-1 cells for studying the anti-inflammatory mechanism of mogrosides. At the same time, a diabetic mouse model was prepared using a high-fat diet and intraperitoneal injection of streptozotocin in order to further study the effects of mogrosides on alleviating symptoms of DKD. Mogrosides can suppress the activation of macrophages and kidney damage in diabetic mice, and this anti-inflammatory effect seems to be mediated through the NF-B/NLRP3/Caspase-1 axis in macrophages. Moreover, the metabolomic results revealed that the anti-inflammatory properties of mogrosides were associated with the modulation of glutamate metabolism and glycerophospholipid metabolism in macrophages. Our results indicated that supplementing diabetic patients with mogrosides may help inhibit inflammatory responses and prevent kidney damage.