In view of the extremely important biological and medicinal properties of napthofurans, the synthesis of these heterocycles has fascinated the interest of medicinal and organic chemists. Keeping this in mind, we herein reporting synthesis, and antimicrobial evaluation of 4-N-aryl -naphtho[2,1-b]furo[3,2-d] pyrimidines 5 (a-l). Structures of these synthesized compounds were confirmed by spectral analysis like IR, NMR and Mass spectrometry. The In vitro antimicrobial activities were reported for the all compounds 5 (a-l). The compounds 5e and 5f exhibited excellent antibacterial, antifungal and antidermatophytic activities against tested pathogens at MIC 3.125, and 3.125g/ml respectively. Furthermore, molecular docking studies of these compounds against Staphylococcus aureus tyrosyl-tRNA synthetase (PDB ID: 1JIJ), S. Aureus Gyrase (PDB ID: 2XCT) and SARS-CoV-2 Omicron (PDB ID: 7TOB), revealed the potential binding mode of the ligands to the site of the appropriate targets. Finally, drug likeness and structures activity relationship studies also disclosed.