Abstract Although the inflammatory response triggered by damage-associated molecular patterns (DAMPs) in the infarcted cardiac tissues after acute myocardial infarction (MI) contributes to cardiac repair, the unrestrained inflammation induces excessive matrix degradation and myocardial fibrosis, leading to the development of adverse remodeling and cardiac dysfunction, although the molecular mechanisms that fine tune inflammation post-MI need to be fully elucidated. Protein phosphatase Mg2+/Mn2+–dependent 1L (PPM1L) is a member of the serine/threonine phosphatase family. It is originally identified as a negative regulator of stress-activated protein kinase signaling and involved in the regulation of ceramide trafficking from the endoplasmic reticulum to Golgi apparatus. However, the role of PPM1L in MI remains unknown. In this study, we found that PPM1L transgenic mice exhibited reduced infarct size, attenuated myocardial fibrosis, and improved cardiac function. PPM1L transgenic mice showed significantly lower levels of inflammatory cytokines, including IL-1β, IL-6, TNF-α, and IL-12, in myocardial tissue. In response to DAMPs, such as HMGB1 or HSP60, released in myocardial tissue after MI, macrophages from PPM1L transgenic mice consistently produced fewer inflammatory cytokines. PPM1L-silenced macrophages showed higher levels of inflammatory cytokine production induced by DAMPs. Mechanically, PPM1L overexpression selectively inhibited the activation of NF-κB signaling in myocardial tissue post-MI and DAMP-triggered macrophages. PPM1L directly bound IKKβ and then inhibited its phosphorylation and activation, leading to impaired NF-κB signaling activation and suppressed inflammatory cytokine production. Thus, our data demonstrate that PPM1L prevents excessive inflammation and cardiac dysfunction after MI, which sheds new light on the protective regulatory mechanism underlying MI.