The present study aimed to investigate the role of quercetin (a naturally occurring chelating agent) and deferoxamine in the gene expression of Cox-1 and TP53 of the heart and FRRSI of the duodenum in iron-overloaded rabbits. To examine whether quercetin and deferoxamine mitigate the change in the level of Cox-1 and TP53 expression in response to iron overload in rabbits, therefore. Twenty-eight rabbits (each group of seven) were used in the current study and treated for 28 days as follows: Group C: Animals in this group were intraperitoneally (IP) injected with normal saline every 72 hours, plus normal saline orally every day as a negative control. In the T1, T2, and T3 groups, the animals in these groups were IP injected with iron dextran (100 mg/kg) every 72 hours. Additionally, the animals in the T2 group were treated with quercetin (350 mg/kg) orally every day, and the animals in the T3 group were injected with deferoxamine (DFO) (125 mg/kg) IM every day. After the end of the experiment, the rabbits were sacrificed, and specimens from the heart and duodenum were obtained to estimate the gene expression of COX-1, TP53, and FRRSI, respectively, using quantitative polymerase chain reaction (qRT-PCR). The results showed a significant increase in fold change in gene expression levels of COX-1 and TP53 in iron overload rabbits (group T1) compared with another group. Also, a significant difference in the level of COX-1 between T2 and T3, while a non-significant difference in the level of TP53 between T2 and T3 was observed. In contrast, the results showed a significant decrease in the level of FRRSI gene expression in group T1 as compared to the other experimental groups, while a non-significant difference was noticed between T2 and T3 for the same gene. Conclusion: The current study suggests using quercetin as an iron chelator is more effective in iron-overloaded rabbits by alleviating the changes in gene expression of COX-1, TP53, and FRRSI in the heart and duodenum