In this research, twenty nine analogues having variable inhibition of E.coli were subjected to quantitative structure activity relationship analysis. Various thermodynamic, electronic and steric parameters were calculated using Chem 3D package of molecular modeling software Chemoffice 8.0. QSAR models were generated employing sequential multiple regression method using in–house statistical program VALSTAT. Statistically significant models with R–values 0.90 were obtained. Models were validated using leave one out and bootstrapping methods. Results obtained shows that stretch energy, dipole-dipole energy, HOMO energy and Non-1, 4 VDW Energy are contributing to biological activity. Findings of present study reveal that substituent those decrease the flexibility of molecule results in increase in antimicrobial potency, aryl substituent would enhance the antimicrobial activity of compounds and presence of electron withdrawing group in structure is favorable for antibacterial activity of triazolothiadiazoles. Keywords: Triazolothiadiazoles; antimicrobials; QSAR; quantitative structure–property relationships.