The macrophage plays a key role in regulating the remodeling of the left ventricle (LV) post-myocardial infarction (MI). However, the underlying regulatory mechanisms of macrophage activations were understudied. The goal of this study, therefore, was to establish a framework for macrophage activations and build a mathematical model based on the framework by integrating computational and experimental approaches. Accordingly, we established a framework including myocytes, monocytes, macrophages, and interlukin-1 (IL-1), IL-10, and tumor necrosis-alpha (TNF-α) based on literature, established a set of ordinary differential equations as the mathematical model, and primarily validated the model with experimental results. This study provides a useful tool to further study macrophage activations.