In this study, three different target analytes from the fruit of myrtle (Rhodomyrtus tomentosa) were extracted via an enzymatic-homogenate synergistic extraction (EHSE) process, and 10 different aqueous solutions of natural surfactants were selected as extraction solvents, thus enabling the simultaneous extraction of piceatannol, resveratrol, and myricetin from the fruit of myrtle (Rhodomyrtus tomentosa). Important factors affecting the yield of piceatannol, resveratrol, and myricetin, including enzyme type, enzyme concentration, pH, surfactant type and dosage, homogenization time, liquid‒solid ratio, incubation and extraction time, incubation time and extraction temperature, were optimized via single-factor experiments. Three important parameters were optimized via the Box‒Behnken design: the liquid‒solid ratio, the incubation–extraction time, and the reaction temperature. The final optimum extraction process conditions were as follows: β-glucosidase concentration, 3.0%, homogenate; time, 3 min; pH, 5; tea saponin concentration, 0.8%; liquid‒solid ratio, 45 mL/g; incubation–extraction time, 2.5 h; and temperature, 67.5 °C. With the optimized experimental parameters, the piceatannol, resveratrol, and myricetin yields were 742.12 ± 37.11 μg/g, 18.58 ± 0.94 μg/g, and 24.83 ± 1.25 μg/g, respectively. Methodological validation and comparison experiments with traditional solvents demonstrated that EHSE is a successful, green, and safe method for extracting active plant components. This approach employs an ecologically benign water-based solution of tea saponin as the extraction solvent, and it combines enzymatic and homogenate procedures to increase extraction efficiency. This study provides a reasonable basis for the application and research of synergistic extraction technology and suggests that more diverse solvent choices should be considered.