Antibiotics, which disrupt essential processes for bacterial growth and proliferation, are crucial in combating bacterial infections. However, their misuse and overuse have resulted in increasing antimicrobial resistance, highlighting the urgent need for new antibiotics. Compounds with a 1,2,4-triazole ring exhibit diverse biological activities, with extensive research demonstrating their significant antimicrobial properties. In silico approaches are used on previously synthesized ninety-five 1,2,4-triazole derivatives against staphylococcus aureus for protein Dihydrofolate reductase (DHFR). The protein Wild-type staphylococcus aureus DHFR in complex with NADPH and Trimethoprim (PDB ID 2W9G), were used for the model development against the S. aureus. Alongside, the four features Ligand based pharmacophore hypothesis and Atom based 3D-QSAR model was generated with statistical parameters include correlation coefficient for the training set (Q2 = 0.7995), regression coefficient for test set (R2 = 0.9808) which proves the reliability of model. Contour visualization was done for the best docked and least docked compound. Furthermore, the best docked molecule was taken and through CheMBL database ligand based virtual screening was performed. Later, ADME/T studies were carried out on top five compounds from the virtual screened database. Among the five compounds, the compounds CheMBL 208844 and CheMBL 275068 were found to be most potent antimicrobial agents against S. aureus. These compounds may be considered as lead for further development of antimicrobial agents.