This systematic review assessed the effectiveness of ozone (O3) in the color change of in-office tooth bleaching in vital teeth (TB) and the sensitivity control. Only randomized controlled clinical trials were included. Seven databases were used as primary search sources, and three additional sources were searched to capture the "grey literature" partially. The JBI tool was used to assess the risk of bias. TB was assessed using the ΔELab color change metric comparing tooth color pre- and post-bleaching. We meta-analyzed the ΔELab estimates per method and calculated the absolute standardized mean difference using random-effect models. The GRADE approach assessed the certainty of the evidence. The ΔELab estimates ranged from 1.28 when the O3 was used alone to 6.93 when combined with hydrogen peroxide (HP). Two studies compared O3 and HP alone, but their TB was similar (SMD = - 0.02; 95%CI: - 0.54; 0.49). The bleaching effectiveness for the combination of O3 + HP compared to HP was similar (SMD = 0.38; 95%CI: - 0.04; 0.81). Thus, based on the available literature, our findings suggest that O3 is not superior to the conventional technique using HP on the change of tooth color. The O3 did not present sensitivity when used alone. When O3 was used in combination with HP, patients reported hypersensitivity only when O3 was applied before HP, i.e., no sensitivity was perceived when O3 was applied after HP.