Myocardial infarction (MI), a major form of coronary artery disease (CAD), triggers a severe inflammatory response in the heart, resulting in increased cell death and adverse ventricular remodeling. Despite treatment advancements, MI remains a significant risk factor for heart failure, underscoring the necessity for a more in-depth exploration of immune cell mechanisms. Proprotein convertase subtilisin/kexin type 7 (PCSK7), expressed in various tissues and immune cells, has been implicated in cardiovascular disease, yet its specific role in cardiac immune cells remains poorly understood. This study aimed to elucidate the role of PCSK7 in MI-related inflammation. Our findings indicate that PCSK7 deficiency reduces circulating cholesterol levels, potentially mitigating infarct injury and improving cardiac function by modulating immune cells. Additionally, PCSK7 promotes macrophage activation and lipid uptake at the ischemic site, intensifying the pathology. We also observed that PCSK7 activates the TNF-α/JNK signaling pathway in macrophages intracellularly, amplifying the inflammatory response. Therefore, targeting PCSK7 in macrophages could help mitigate post-MI inflammation, alleviate disease severity, and offer novel therapeutic strategies for patients with CAD.