Abstract: in recent years, the global use of benzodiazepines (BZDs) and designer benzodiazepines (DBZDs) has significantly increased. In order to effectively monitor and control the presence of benzodiazepines in specific regions, a method combining solid phase extraction (SPE), ultra-performance liquid chromatography (UPLC), and triple quadrupole mass spectrometry (MS/MS) was developed. The optimization process involved the pretreatment process and UPLC-MS/MS parameter adjustments. The pretreatment optimization included the selection of appropriate SPE columns, flushing and elution conditions, and resolution conditions. Subsequently, this method was applied to analyze the influent samples from six wastewater treatment plants in Beijing. The results showed that: (1) The most favorable outcomes were achieved using the Cleanert PCX extraction column, along with 2 mL of 2% formic acid solution, 2 mL of methanol for flushing, 4 mL of 5% methanol ammonia solution for elution, and 500 μL of a 50% methanol-water solution for residue redissolution after evaporation. (2) By using these optimized conditions, the recovery rates of 25 target compounds in various concentration ranges were between 85.7% and 115%. The matrix effect, limits of detection and quantification, linear relationship, precision, and other performance indicators all met validation criteria. (3) The real influent samples showed the detection and quantification of 18 out of the 25 target compounds, with concentrations ranging from 0.03 to 22.4 ng/L. The results indicate that the developed method can detect both BZDs and DBZDs in wastewater samples, which can serve as a valuable tool for further research on BZDs and DBZDs using wastewater-based epidemiology.