Abstract: The aim of this study was to analyze and model the 3D structure PB2 protein of influenza A viruses of subtype H5N1 and predicting the most effective drug against influenza virus (subtype H5N1) from a list of available drugs by targeting PB2 protein. This was done first by database search of PB2 protein sequence which results in a sequence of 759 amino acids (Acc. No. ACZ58135). 3D structure of PB2 protein was not available in PDB database, therefore template structure (PDB ID: 2vqzD) with 92.727% sequence identity was selected. Homology model was constructed using Swiss Model and validated using PROCHEK. Ramchandran plot analysis shows 87.1% of the residues in the most favored region. The model was finally docked with three different drugs namely Rimantadine, Amantadine and Zanamivir. From the docking result it was observed that the drug rimantadine had the least binding energy and considered as the most effective drug against PB2 protein. The study is unique in nature as there is no known report available about the homology modeling of PB2 protein as well as its docking with known drugs. All work was done using in silico approaches.