The present study aimed to evaluate the antibacterial effect and the antioxidant potential of quercetin nanoparticles on drug-resistant E. coli O157 in New Zealand White Rabbits. Initial surveillance lasting two years (2018-2019) was performed to isolate and molecular detection of some virulence genes of some drug-resistant E.coli strains circulating in NZW rabbits in Egypt.The selected E.coli O157 strain in our experimental work produced strong biofilm and sxt1 (MN902223), sxt2 (MT832770) and eaeA (MN813493) (similarities were 99-100% compared to other E. coli O157 strains in gene bank). The most important results of experimental work in the present study showed that rabbits treated with quercetin nanoparticles showed neither clinical signs nor post mortem lesions. E. coli O157 was re-isolated only at 3 dPI in comparison to that in other experimental infected groups. The groups of rabbits treated with quercetin and nano-quercetin showed a significant increase in antioxidant enzymes before and after infection and in comparison with quercetin, the highest activity in GPX and SOD level appeared in nano-quercetin group at 10 dPI, while at 3 dPI the lowest activity in MDA appeared in NQ group compared to other groups. There were no significant changes in biochemical parameters except nano-quercetin group showed a significant decrease in total cholesterol at 3,10 dPI. In conclusion, Quercetin nanoparticles could be used as a preventive therapeutic agent and a powerful antioxidant drug for protection against E. coli O157.