Obesity cardiomyopathy, an important complication of obesity, is characterized by chronic inflammation that infiltrates the heart continuously. Elevated levels of free fatty acids (FFAs) in obese patients can activate the nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways in the heart, triggering inflammatory responses that lead to myocardial hypertrophy and fibrosis. Fisetin, a natural flavonoid, possesses strong anti-inflammatory and antioxidant properties. Therefore, we hypothesized whether Fisetin could alleviate obesity-induced cardiac inflammation by inhibiting the NF-κB and MAPK signaling pathways. We evaluated the effects of Fisetin treatment on obesity cardiomyopathy both in vitro and in vivo, and the results showed that Fisetin significantly inhibited palmitic acid (PA)-induced levels of myocardial pro-inflammatory cytokines tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1 beta (IL-1β). This effect was dependent on the inhibition of the NF-κB and MAPK signaling pathways. Additionally, in C57BL/6J mice fed a high-fat diet (HFD), Fisetin was found to reduce cardiac inflammation, myocardial hypertrophy, and fibrosis by inhibiting the NF-κB and MAPK signaling pathways. In conclusion, we discovered that Fisetin can regulate cardiac inflammation by inhibiting the NF-κB and MAPK signaling pathways, thereby treating obesity cardiomyopathy and offering a new candidate drug for its therapy.