N-Acylethanolamine acid amidase (NAAA) is a cysteine enzyme that catalyzes the hydrolysis of palmitoylethanolamide (PEA). Pharmacological blockage of NAAA elevates PEA levels and exerts powerful anti-inflammatory activities. We have recently identified a highly potent NAAA inhibitor F215. Here, we demonstrated that F215 was an unusual inflammation-restricted NAAA inhibitor. In lipopolysaccharides (LPS) induced acute lung injury (ALI) model, F215 markedly accelerated inflammation resolution, promoted clearance of neutrophils infiltration and alveolar repair in the lungs. F215 efficiently inhibited NAAA and protected endogenous PEA from degradation in ALI model, but it cannot readily suppress the NAAA activity in naïve mice. The inflammation-restricted effect of F215 was further confirmed in the alveolar macrophage, F215 only increased PEA levels and exerted anti-inflammatory effects in activated macrophages, but not in unstimulated macrophages. Moreover, we also showed that the pharmacological effects of F215 were restricted to the local inflamed skin elicited by 12-o-tetradecanoylphorbol-13-acetate (TPA), but not the normal tissues. We believe that F215 could be a useful probe to investigate the function of NAAA, as well as a potent anti-inflammatory agent, and its inflammation-restricted feature might offer a new approach to prevent potential side effects of systemic enzyme inhibition.