Abstract: This study established a multi-residue analytical method for pesticides in soil based on QuEChERS pretreatment coupled with high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS), and applied it to determine the residue levels of 41 pesticides and 3 metabolites in surface soil samples collected from farmland in the Tarim River Basin, an arid region in northwestern China. Results showed that a total of 11 pesticides were detected in the collected soil samples. Boscalid (37.1%) was the most frequently detected, followed by pendimethalin (18.6%), carbendazim (8.6%), thiamethoxam (8.6%), oxyfluorfen (4.3%), paclobutrazol (4.3%), pyraclostrobin (2.9%), azoxystrobin (2.9%), prochloraz (1.4%), atrazine (1.4%), and epoxiconazole (1.4%). The concentrations of all detected pesticides at the sampling point ranged from 10.5 to 809.4 μg/kg. Across the entire study area, boscalid had the highest mean concentration (21.2 μg/kg), followed by acetochlor (11.5 μg/kg), pendimethalin (9.1 μg/kg), and carbendazim (8.5 μg/kg). Furthermore, the Risk Quotient (RQ) model was employed to assess ecological risk levels by calculating the ratio of the measured pesticide concentration to the Predicted No-Effect Concentration (PNEC) derived from multi-trophic level data. Ecological risk assessment indicated that nicosulfuron, oxyfluorfen, pyridaben, chlorbenzuron, and sulfentrazone pose a high risk to agricultural soils in the Tarim River Basin. In contrast, boscalid showed a high risk in localized areas, while several other pesticides presented a moderate risk level. In conclusion, pesticide residues are present in the agricultural soils of the Tarim River Basin, and their potential threat to the fragile ecosystem of this arid region cannot be overlooked. This study provides an important scientific basis for regional chemical pesticide management and sustainable agricultural development.