Quercetin has multiple protective effects against cardiometabolic diseases, but the biological mechanisms underlying the benefits in diabetic cardiomyopathy (DCM) are unclear. A mouse DCM model was established by high-fat diet (HFD, 8 months) combined with streptozotocin injection (at the mid-feeding), and quercetin (100 mg per kg per day) was administrated orally after streptozotocin. Our major results indicated that the cardiac ejection fraction and fractional shortening, mRNA levels of Collagen I and CTGF, and the protein expression levels of NLRP3, caspase-1, IL-1β, and IL-18 were reduced (P < 0.05) in DCM mice in response to quercetin intervention. Serum metabolomic analyses identified glycerophospholipid metabolism as the main pathway implicated in the cardiac benefits of quercetin in DCM. Such findings showed that quercetin may ameliorate cardiac dysfunction and myocardial fibrosis via reducing inflammatory actions and the glycerophospholipid metabolism dysregulation in DCM.