A modified quick, easy, cheap, effective, rugged and safe (QuEChERS) pretreatment method combined with ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was developed for the simultaneous determination of seven cucurbitacins in oriental melon. The samples were extracted with acetonitrile. After centrifugation, 1 mL of the supernatant was cleaned up with 50 mg of primary secondary amine (PSA) and 50 mg of octadecylsilane (C₁₈). The separation was performed on a Waters XBridge C₁₈ column with gradient elution using acetonitrile as mobile phase A and 0.1% formic acid in 5 mmol/L ammonium acetate aqueous solution as mobile phase B. The detection was accomplished by multiple-reaction monitoring scanning in a positive/negative ion-switching electrospray ionization mode. The cucurbitacin compounds were separated within 16 min. Good linearity was achieved for all analytes in the concentration range of 0.1-1500 μg/L with correlation coefficients greater than 0.99. The recoveries at spiked levels of 20.0, 100.0 and 500.0 μg/kg were between 75.7% and 118.3%, and the precision, expressed as relative standard deviation (RSD), ranged between 0.5% and 13.6%. The limits of detection (LOD) were between 0.16 and 4.33 μg/kg, and the limits of quantitation (LOQ) were between 0.27 and 13.11 μg/kg. We concluded that this method has the advantages of simple pretreatment, high sensitivity, precision and accuracy, and short analysis time, and is suitable for simultaneous determination of the seven cucurbitacins in oriental melon.