Abstract: To clarify whether Eriochloa villosa populations in soybean fields have developed resistance to quizalofop-p-ethyl and to investigate the non-target mechanisms underlying this resistance. The resistance levels to quizalofop-p-ethyl of 27 E. villosa populations collected from soybean fields in Liaoning and Heilongjiang Provinces were evaluated with the method of whole-plant bioassays. The non-target resistance mechanisms were analyzed from the perspectives of detoxification metabolism enzymes and differential absorption/metabolism through efficiency enhancement test of detoxification enzyme inhibitor, enzyme activity comparisons, and HPLC detection. The results indicated that GR₅₀ values of E. villosa to quizalofop-p-ethyl ranged from 9.64 to 163.19 g/hm². Among 27 populations, 37.04% showed sensitivity, 11.11% exhibited low-level resistance, 51.85% showed moderate-level resistance, and no high-level resistance. The most resistant population of TL5 displayed cross-resistance to other ACCase-inhibiting herbicides, including haloxyfop-p-methyl, and multiple resistance to the ALS-inhibitor nicosulfuron and the HPPD-inhibitor mesotrione. Treatment with the cytochrome oxidase P450 (P450) inhibitor piperonyl butoxide (PBO) and the glutathione S-transferase (GST) inhibitor 4-chloro-7-nitro-2,1,3-benzoxadiazole (NBD-Cl) increased the susceptibility of resistant E. villosa to quizalofop-p-ethyl, reducing the value of GR₅₀. Following quizalofop-p-ethyl application, the activities of P450 and GST in resistant populations increased substantially and were significantly higher than those in susceptible populations. HPLC detection revealed that the absorption of quizalofop-p-ethyl in leaves was similar between resistant and susceptible populations. However, the metabolic rate of quizalofop-p-ethyl in the resistant populations was significantly higher than that in the susceptible population. This study confirms that enhanced metabolism mediated by P450 and GST is the primary cause of non-target site resistance to quizalofop-p-ethyl in E. villosa.