The anti-inflammatory and immunomodulatory properties of Harungana madagascariensis(HM) leaf extract was experimentally investigated and the electronic structure property of the GC–MS identified phytochemicals was carried out theoretically. Solvent extracts from the leaf were prepared and evaluated for activities using standard methods. Subsequently, phytochemicals in the most biologically active extract were identified using TLC/GC–MS. The ability to reduce inflammation, hematological response and antibody titre in the serum were used for evaluating the immunomodulatory activity. The DCM extract showed a better anti-inflammatory activity than other fractions by inhibiting carrageenan induced paw edema by 90.95%, and 67.33% respectively at 200 and 400 mg/kg and reducing xylene induced ear weight from 0.025 ± 0.003 to 0.006 ± 0.002 mg (76% effectiveness) and 0.008 ± 0.002 mg (68% effectiveness) respectively at 200 and 400 mg/kg. The DCM fraction yielded 27 compounds by the GC–MS analyses which were mostly fatty acids and their derivatives. The low HOMO–LUMO energy gaps and high electrophilicity indexes obtained for the identified phytochemicals support the experimental results and hence, confirms the suitability of HM-based phyto-drug as anti-inflammatory and immunomodulatory agents against proliferation and hyper-sensitivity.