High fructose consumption leads to metabolic syndrome and enhances cardiovascular disease risk. However, our knowledge of the molecular mechanism underlying the cardiac disease caused by fructose feeding is still poor. Nod-like receptors (NLRs) are intracellular sensors, responding to a variety of intracellular danger signals to induce injuries. NLRP4 is a negative regulator of nuclear factor-κB (NF-κB) signaling pathway through interactions with kinase IκB kinase (IKK). Here, we illustrated that NLRP4 attenuates pro-inflammatory cytokines releasing, including Transforming growth factor (TGF-β1), Tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-18 (IL-18) and interleukin-6 (IL-6), in fructose-treated cardiac cells by means of RT-qPCR, and western blotting analysis. In addition, NLRP4 could reduce the expression of TANK-binding kinase 1/interferon regulatory factor 3 (TBK1/IRF3), reducing inflammation response and achieving its anti-hypertrophic action. TBK1 plays critical roles in the IRF3 signaling pathway, modulating inflammation response. The inhibition of IKK/NF-κB signaling pathway by NLRP4 is confirmed by NLRP4 over-expression and knockdown. In vivo, high fructose feeding induced cardiac injury, accompanied with reduced expression of NLRP4 in heart tissue samples, indicating the possible role of NLRP4 in ameliorating heart injury. In conclusion, the findings above indicated that NLRP4 is an important mediator of cardiac remodeling in vitro and in vivo through negatively regulating TBK1/IRF3 and IKK/NF-κB signaling pathways, indicating that NLRP4 might be a promising therapeutic target against cardiac inflammation.