Skeletal muscle regeneration upon injury is an active process that is highly orchestrated by immune cells and mechanistically depends on the great level of coordination between biological processes. Indispensable of the regeneration process is the initial inflammation that consists of two phases, initiation and resolution, which are coordinated by metabolites that can mediate it. Lipid mediators have signaling mediated capacities, and here we showed that there is a dynamic regulation of the mediator lipidome, which was consistent in a model of acute sterile injury, and also in a more pathophysiological model upon exercise. We also monitored a marked remodeling of structural lipids, which can act as biosynthetic sources of the lipid mediator pool. Lipid mediators changed dynamically in regard to their biosynthetic sources. We also observed epigenomic alternations during the time course of inflammation. Consistent with these changes was the actively changing transcriptome, which was recapitulated in infiltrating macrophage populations. In conjunction with our observations we asked whether a lipid biomolecule, RvD2, could affect the temporal regulation of macrophage phenotypic switch. Interestingly, we found that RvD2 can facilitate this switch in vivo, enhancing the reparative macrophages populations over their pro-inflammatory counterparts. As a result, through the effector actions of RvD2, regeneration of the injured skeletal muscle tissue was promoted as it was shown through in vivo force measurements in a model of delayed regeneration in mice.