High hydrostatic pressure as a kind of non-thermal processing might maintain the quality of thermo-sensitive watermelon juice. So, the effect of high hydrostatic pressure treatment on enzymes and quality of watermelon juice was investigated. After high hydrostatic pressure treatment, the activities of polyphenol oxidase, peroxidase, and pectin methylesterase of juice decreased significantly with the pressure (P < 0.05). Inactivation of polyphenol oxidase and peroxidase could be fitted by two-fraction model and that of pectin methylesterase could be described by first-order reaction model. Titratable acidity, pH, and total soluble solid of juice did not change significantly (P > 0.05). No significant difference was observed in lycopene and total phenolics after high hydrostatic pressure treatment when compared to the control (P > 0.05). Cloudiness and viscosity increased with pressure (P < 0.05) but did not change significantly with treatment time (P > 0.05). a*- and b*-value both unchanged after high hydrostatic pressure treatment (P > 0.05) while L*-value increased but the values had no significant difference among treated juices. Browning degree after high hydrostatic pressure treatment decreased with increase in pressure and treatment time (P < 0.05). Through the comparison of total color difference values, high hydrostatic pressure had little effect on color of juice. The results of this study demonstrated the efficacy of high hydrostatic pressure in inactivating enzymes and maintaining the quality of watermelon juice.