Unravelling the precise mechanisms underlying the anti-inflammatory action of fruit extract of Pithecellobium dulce (FPD) is quite complex. Hence the prime approach of this particular study is to unveil intriguing insights to its possible anti-inflammatory mechanisms. Anti-inflammatory effects of FPD were determined against experimentally induced acute and chronic inflammation in mice paw edema models. Administration of FPD significantly reduced the acute and chronic inflammation via regulating pro-inflammatory mediators such as pro-inflammatory cytokines (TNF-α, IL-6, and IL-1ß), Cycloxygenase 2 (COX-2), and inducible nitric oxide synthase (iNOS) compared to control group. The overall results suggest that FPD mitigates inflammation by regulating the inflammatory mediators. PRACTICAL APPLICATIONS: Fruit of Pithecellobium dulce is comestible and has been widely distributed in Asian pacific region. Non-steroidal anti-inflammatory drugs (NSAIDS) are among the most conventional treatment strategy against pain and inflammation. Although, chronic use of NSAIDS are associated with severe side effects such as gastrointestinal irritation, hepatic injury, excessive bleeding, and cardiovascular disorders. Hence identification of more effective complementary and alternative therapeutic approach from natural resources with fewer side effects could improve the quality of life of those receiving NSAIDS. Administration of fruit extract of Pithecellobium dulce ameliorates carrageenan-induced acute inflammatory responses, as evidenced by paw edema measurement, expression of antioxidant enzymes such as glutathionine, super oxide dismutase, pro-inflammatory cytokine analysis (IL-1β, IL-6, and TNF-α), vascular permeability measurement, expression of COX-2 and iNOS. Further, confirmed the involvement of HO-1 pathway in anti-inflammatory action of FPD. The outcome of this present investigation could have a broad range of applications in alleviating inflammatory disorders.