The thermostable cucurbitacin A and B from mature fruit of wild cucumber (Cucumis myriocarpus) and wild watermelon (Cucumis africanus), respectively, are used in product development for various industries. Mature fruit from wild cucumber and wild watermelon suffer from high incidents of postharvest decays. Drying fruit at the recommended temperatures of 30 to 40 °C for medicinal plants resulted in molds developing on the material, with optimum temperature to prevent decays being at 52 °C. The influence of 52 °C and higher temperatures on active ingredients in the two fruit had not been documented. The objective of this study, therefore, was to determine the relative effects of increasing drying temperatures above the 52 °C standard on concentrations of cucurbitacin A and B in fruit of wild cucumber and wild watermelon. Fruit pieces were oven-dried at 52, 60, 70, 80, 90, and 100 °C for 72 hours. Relative to 52 °C, higher temperatures resulted in 25% to 92% less cucurbitacin compared with the maximum produced at 60 °C. In contrast, relative to 52 °C, higher temperatures reduced concentrations of cucurbitacin B by 47% to 86%. In conclusion, the compromise temperature of 52 °C for preserving fruit pieces in wild cucumber and wild watermelon from decay should also be viewed as the optimum temperature for preserving cucurbitacin A and B.