Acute lung injury (ALI) is a syndrome characterized by acute local and systemic inflammation associated with high morbidity and mortality rates. This substantial progression involves neutrophil activation and migration into injured sites. Formyl peptide receptors (FPRs) are mainly expressed on leucocytes and sense microbe-associated molecular pattern (MAMP) molecules, thereby regulating leukocyte chemotaxis and activation. The formyl peptide receptor 2 (FPR2) selective agonist WKYMVm (Trp-Lys-Met-Val-D-Met) has shown potent pro-angiogenic, anti-inflammatory, and anti-apoptotic properties. However, the pivotal role of WKYMVm and its related signaling cascade is not fully understood in ALI. Therefore, in this study, we investigated whether WKYMVm exhibits bactericidal activity during neutrophil accumulation in acute lung injury (ALI) in mice. A daily intraperitoneal treatment of ALI mice with WKYMVm (2.5- and 5 mg/kg/d) daily over four days decreased the levels of proinflammatory cytokines TNF-a, IL-6, and IL-1b. We demonstrated an anti-inflammatory effect of WKYMVm peptide with distinct IFN-g expression, lasting MPO and NO release, and SOD activation resulting in enhanced antimicrobial action of neutrophils. In sum, FPR2 ligands, including WKYMVm, could be a therapeutic choice to modulate neutrophils in acute inflammation. Taken together, our data suggest therapeutic potential of WKYMVm, via FPR2-dependent regulation of STAT1/IRF1, in ALI.