The growing popularity of e-cigarettes has raised significant concerns about the safety and potential abuse of these products. Compounds originally used in the medical field, such as etomidate, metomidate, and isopropoxate, have been illegally added to e-liquids, posing substantial risks to consumer health, and facilitating the misuse of illicit drugs. To address these concerns, this study developed a rapid and efficient method for detecting etomidate, metomidate, and isopropoxate in e-liquids using thermal desorption electrospray ionization coupling triple quadrupole mass spectrometry (TD-ESI/MS/MS). The TD-ESI/MS/MS method exhibits high sensitivity, with detection limits for etomidate, metomidate, and isopropoxate reaching 3 ng/mL. Screening of 70 seized e-liquid samples from 12 cases using TD-ESI/MS/MS revealed that 46 samples contained only etomidate, 13 samples contained only isopropoxate, and 11 samples contained both etomidate and metomidate. The qualitative results obtained from TD-ESI/MS/MS were in complete agreement with those of GC-MS. Moreover, the TD-ESI/MS/MS method requires no pre-treatment steps and has a detection time of only 1 min, thereby saving experimental consumables and significantly reducing detection time. The method demonstrated high sensitivity, accuracy, and reproducibility, making it suitable for high-throughput screening in forensic and regulatory settings.