The metabolic resistance of plants to herbicides is similar to the herbicide metabolism process accelerated by safeners. The tolerance to fenoxaprop-P-ethyl (FE) is distinct among different varieties of rice in which phytotoxicity forms easily, resulting in the restricted use of FE in paddy. Safener effectively resolves this issue. This study showed that rice 9311 and Meixiangzhan No. 2 (MXZ) had different tolerance mechanisms to FE. Isoxadifen-ethyl hydrolysate (IH) alleviated FE the inhibition of rice growth. Transcriptome sequencing revealed numerous differentially expressed genes (DEGs) between the two varieties. A total of 31 metabolic enzyme genes related to herbicide detoxification were screened by analyzing the DEGs in different rice varieties or treatments. The results of the quantitative reverse transcription polymerase chain reaction indicated that 12 genes were potential metabolic genes resistant to FE in rice. Additionally, the enhanced expression of GSTU6, DIMBOA UGT BX8, and ABCG39 was confirmed to be induced by safener. Taken together, our results demonstrated that the induced expression of these three genes might be crucial for resistance to herbicide phytotoxicity in crops. These results may help us to understand herbicide metabolism in crops and to develop novel strategies for the safe use of herbicides. [ABSTRACT FROM AUTHOR]