Surface defect engineering strategies are critical for catalytic activity, especially in the photodegradation of organic pollutants. However, the exact function of the oxygen vacancies for the photooxidation performance of ZnO is unclear. Oxygen vacancies might act as electron donors to encourage carrier separation and then boost catalytic efficiency; besides, excessive oxygen vacancies might act as recombination centers for photogenerated electron–hole, which impairs photocatalytic performance. Therefore, the specific effect of the amount of oxygen vacancies in ZnO needs to be investigated. We developed a facile method, which is inspired by the aforementioned strategy, to adjust the amount of oxygen vacancies in ZnO nanosheets for exploring its photocatalytic activity. ZnO nanosheets with oxygen vacancies of low density exhibit a greatly enhanced photooxidation ability and can rapidly and stably degrade high concentration (4 × 10−4 mol/L) of phenol compared with nearly inactivity of the ZnO nanosheets with plentiful oxygen vacancies. This mechanism of the improved photocatalytic activity is proposed to be mainly due to the significant reduction in oxygen vacancies as carrier recombination centers and the increase in photogenerated electron–hole mobility. This research presents a new idea for the surface defect engineering design of regulated photocatalysts to enhance photocatalytic activity.