Objective: To evaluate the effect of COVID-19 preventive mouthwashes on the surface hardness, surface roughness (Ra), and color change (Delta E) of three different polymer-based composite CAD/CAM materials (Vita Enamic (ENA), Grandio Block (GB), Lava Ultimate (LU)). Methods: A total of 100 rectangular-shaped specimens with dimensions of 2 mm x 7 mm x 12 mm were obtained by sectioning three different CAD/CAM blocks and randomly divided into five subgroups according to the 30 days of mouthwash immersion protocol as follows: Control: artificial saliva, PVP-I: 1% povidone-iodine, HP: 1.5% hydrogen peroxide, CPC: mouthwash containing 0.075% cetylpyridinium chloride, EO: mouthwash containing essential oils. Microhardness, Ra, and Delta E values were measured at baseline and after 30 days of immersion protocols. Data were analyzed using the Wald Chi-square, two-way ANOVA, and post hoc Tukey tests. Results: The independent factors (materials and solutions) significantly influenced the microhardness and color (p < 0.001). Ra of the materials was not affected by any of the mouthwashes (p > 0.05). The microhardness and color of each material varied significantly after immersion in PvP-I and HP (p < 0.05). The highest percentage change in microhardness, Ra, and Delta E was found in LU immersed in PvP-I and HP mouthwashes, while the lowest change was found in ENA groups (p < 0.05). Conclusion: Within the limitations of this study, it was found that the surface hardness and color of tested polymer-based composite CAD/CAM materials are susceptible to degradation and change after 30 days of immersion in 1% PvP-I and 1.5% HP mouthwashes.