Zn as an essential element has the potential to protect against mercury (Hg) toxicity in rice. However, the antagonistic effects between Zn and Hg in rice and their mechanisms remain unknown. This study proposed a promising strategy for Zn application to mitigate Hg accumulation and toxicity in rice and revealed the underlying molecular mechanisms. The findings revealed that Zn supplementation significantly reduced the uptake and transportation of both IHg and MeHg in rice, thereby alleviating Hg phytotoxicity. In particular, Zn profoundly mitigated Hg-induced oxidative damage to rice, which was attributed to the redistribution of Hg and Zn in the root and Zn competing for binding sites on glutathione. The co-binding of Zn2+ and HgCH3+ within the same active sites of Zn transporters can promote the transfer of regions with a high charge density distribution at the highest occupied molecular orbital (HOMO) level. This process facilitates proton attack on the Hg-C bond, thereby enhancing MeHg demethylation in rice. By elucidating the molecular mechanisms of Zn, IHg, and MeHg interactions in rice, this study offers new insights for developing efficient strategies to mitigate Hg risks while boosting the Zn content in crops, thereby fortifying food safety.