This investigation elucidates the spatiotemporal dynamics of NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activation following myocardial infarction (MI), a process that has not been fully characterized. We revealed early activation of the NLRP3 inflammasome in mice with MI and characterized its dynamic temporal expression. Notably, the knockout and inhibition of Nlrp3 expression were found to significantly mitigate infarct size and enhance cardiac function. Furthermore, our analysis of the spatial characteristics of inflammasome activation revealed predominant activation in macrophages and subsequent activation in fibroblasts on the third day post-MI. To elucidate the nexus between macrophage-associated NLRP3 inflammasome activation and myocardial fibrosis, we employed targeted metabolomics analyses of inflammatory oxylipins, small interfering RNA (siRNA) interference experiments, and various molecular assays. These findings revealed that macrophage-associated inflammasome activation facilitates the conversion of fibroblasts into myofibroblasts via the 15-hydroxy-5,8,11,13-eicosatetraenoic acid (15-HETE)-mediated small mother against decapentaplegic (Smad) pathway. Additionally, both mass spectrometry imaging (MSI) and targeted metabolomics analyses confirmed the significant increase in 15-HETE levels in mice with MI and in patients with MI and acute coronary syndrome (ACS). Our comprehensive dataset suggests that NLRP3 inflammasome activation in MI is characterized by distinct temporal and spatial patterns. These insights mark a significant advancement toward precise MI prevention and treatment strategies, particularly early myocardial fibrosis intervention.