Inflammation is a natural host defensive process that is largely regulated by macrophages during the innate immune response. Mitogen‐activated protein kinases (MAPKs) are proline‐directed serine and threonine protein kinases that regulate many physiological and pathophysiological cell responses. p38 MAPKs are key MAPKs involved in the production of inflammatory mediators, including tumor necrosis factor‐α (TNF‐α) and cyclooxygenase‐2 (COX‐2). p38 MAPK signaling plays an essential role in regulating cellular processes, especially inflammation. In this paper, we summarize the characteristics of p38 signaling in macrophage‐mediated inflammation. In addition, we discuss the potential of using inhibitors targeting p38 expression in macrophages to treat inflammatory diseases.