The current research is engrossed on screening anti-inflammatory activity of methanolic grain extract of Pennisetum glaucum using in silico, in vitro and in vivo methods. In silico studies were carried out using docking (CB-Dock2), Ramchandran plot (procheck). In vitro studies were carried out using inhibition of protein denaturation, membrane stabilization activity while in vivo studies using carrageen induced paw edema in rodents. Docking studies were performed for natural compounds against PDB ID: 1FT4, PDB ID: 3NS7, PDB ID: 1KQU and PDB ID: 3E7G. The docking results revealed that all of the selected proteins had the greatest vina scores with all of the phytoconstituents from the extract and the common medication indomethacin, indicating a better receptor-ligand binding affinity. In in vitro results MEPG showed higher inhibition at 500µg/ml (46.4%) compared to aspirin 100µg/ml (60.7%) for protein denaturation. The extract demonstrated 56.6% suppression of heat-induced hemolysis at 500 g/ml, while aspirin demonstrated 73.3% inhibition at 100 g/ml. The extract inhibited hypotonicity-induced hemolysis by 59.3% at 500 g/ml and Diclofenac sodium 100 g/ml with 75% inhibition at 100 g/ml. The extract at doses of 200 mg/kg, 400 mg/kg, and the common medicine indomethacin at 3 mg/kg bd.wt significantly reduced paw edoema in an animal model. It is clear from the above that Pennisetum glaucum methanolic grain extract had strong anti-inflammatory activity.