The biological evaluation, QSAR and docking studies ofNaphthyridine derivatives are carried out to optimize their inhibitory activity against DNA topoisomerase. The biological activities of these derivatives are correlated to different molecular properties. The AM1and PM3 semi empirical methods are used to estimate vertical ionization potentials (IPv’s), electron affinity (EA) , electro negativity (χ), hardness (η), softness (S), electrophilic index (ω), partition coefficient (LogP),hydration energy(HE), ionization potential(IP) and charges. The different modeled equations are proposed by regression analysis. The leave-one-out cross-validation method is used to estimate the predictive power of final QSAR equations. The hardness (η), was found to be indicative molecular property by regression analysis. Docking studies of naphthyridines with DNA topoisomerase were made to support the finding of QSAR studies. Analysis of results of both QSAR and Docking studies suggested that remarkable inhibitory activity is exhibited by molecule 5, 7, and8.The hydrogen bond interactions along with hydrophobic and electrostatic interactions are mapped to confirm their potencies.