Previously synthesized 2,5-disubstituted benzoxazole and benzimidazole derivatives, were tested for their genotoxic activity in the Bacillus subtilis rec- assay. The results revealed that 5-methyl-2-(p-aminobenzyl) benzoxazole exhibited the highest genotoxic response, which was comparable to 4-nitroquinoline 1-oxide (4-NQO), the reference agent of classical positive mutagen. Among the other tested compounds, four showed a genotoxic activity. A QSAR study revealed that structural parameters IYC2H4 and IYCH2O, indicating the bridge elements between the phenyl moiety and the fused ring system at position 2 and the quantum chemical parameter (Delta E), showing the difference between HOMO and LUMO energies, were found significant for enhancing the genotoxic activity in these compounds. In addition, the substituent effects on positions R and R-1 were found important for the activity as well as holding a substituent possessing a maximum length with a minimum width property on position R1 like alkyl groups. On the other hand, substituting position R with an electron donating group instead of electron withdrawing group increased the genotoxic activity.