Objectives: This study aimed to evaluate and compare the effect of plasma treatment versus conventional treatment on the micro shear bond strength (μSBS), surface roughness, and wettability of three different CAD/CAM materials. Materials and methods: Sixty cylindrical specimens (5 mm diameter ×3 mm height) were prepared from three different CAD/CAM materials: Group A: Zirconia, Group B: Lithium disilicate, and Group C: Resin nano-ceramic. Each group was subdivided into two subgroups according to surface treatment used: Subgroup I: Conventional treatment, zirconia was sandblasted with Al2O3, while lithium disilicate and resin nano-ceramic were etched with hydrofluoric acid. Subgroup II: Plasma treatment, the surface of each material was treated with a plasma device (PiezoBrush® PZ3 Handheld Device, Relyon Plasma, Regensburg, Germany). G-Multi PRIMER was applied, then self-adhesive cement (G-CEM ONE) was applied using a split mold (1 mm diameter ×3 mm height), and μSBS was tested in a universal testing machine. The surface roughness was measured using a profilometer. Nine additional specimens of each material for wettability test using an optical tensiometer. Statistical analysis: The data were analyzed using ANOVA and Bonferroni test at a level of significance of 0.05. Results: The highest mean of μSBS was recorded by AII (27.3 MPa), while the lowest was recorded by AI (17.9 MPa). One-way ANOVA test revealed a significant difference among groups. Bonferroni test showed each two subgroups significant difference except subgroups AI, CI and BII, CII, where there was a non-significant difference. For all CAD/CAM materials, conventional treatment increased the surface roughness compared to plasma treatment, while the contact angle decreased after plasma treatment. Conclusion: Plasma treatment increased the μSBS of resin cement to zirconia significantly while not significantly affecting the μSBS of resin nano-ceramic. Conventional treatment of lithium disilicate provided significantly higher μSBS than plasma treatment.