Air-polishing powders are used to remove stains from the enamel and various restorative materials, but their effect on the discoloration of CAD/CAM blocks remains scarce. Therefore, this study investigated the effect of various air-polishing powders on the color changes in different CAD/CAM blocks to predict the esthetic outcomes. Specimens were prepared from CAD/CAM blocks (Vita Mark II, Paradigm MZ100, Lava Ultimate, Cerasmart, Vita Enamic) and divided into five groups (n = 10) according to the air-polishing powder: sodium bicarbonate; aluminum trihydroxide; calcium carbonate; glycine; and erythritol. Color parameters were measured with a spectrophotometer before and after air-polishing. The color difference was calculated with the ΔE00 formula. Data were statistically evaluated with one-way ANOVA, Tukey, and two-way ANOVA tests (α = 0.05). The CAD/CAM block type and the air-polishing powder type significantly influenced the ΔE00 value, whereas their interactions did not affect it significantly. Calcium carbonate and aluminum trihydroxide significantly increased the ΔE00 values of Lava Ultimate and Cerasmart. Although none of the groups exceeded the acceptability threshold (ΔE00 = 1.8), most exceeded the perceptibility threshold (ΔE00 = 0.8). Consequently, dentists should avoid air-polishing or should repolish with care, depending on restorative material knowledge, to maintain color stability when uncertain about the material encountered clinically.