The aim of this study was to assess the influences of different CAD/CAM ceramic compositions and thicknesses on the surface roughness and hardness of ceramic restorations. Four different ceramics were used in the current study: lithium disilicate (LD), leucite reinforced (LE), advanced lithium disilicate (ALD), and zirconia-reinforced lithium silicate (ZLS). Each group included 30 specimens subdivided into three different ceramic thicknesses (0.5, 1 and 1.5 mm thicknesses). The microhardness was measured for all the specimens using a microhardness testing machine, while the surface roughness was measured using a non-contact optical profilometer at three intervals (before toothbrushing and after toothbrushing, with and without toothpaste). Three-way and two-way ANOVA were used to determine the factors influencing the surface roughness and microhardness. There was a significant difference in the surface roughness between the studied groups for all the thicknesses. The findings showed that ALD had the lowest surface roughness, while ZLS showed the highest surface roughness. Moreover, ALD, followed by ZLS, had the highest hardness, while LD and LE had the lowest hardness values. Regarding the thicknesses, both the 0.5 and 1 mm ceramic thicknesses showed a significantly lower surface roughness than the 1.5 mm thickness, while the 1.5 mm thickness showed a significantly higher microhardness than the 0.5 mm thickness. The surface roughness and hardness were significantly affected by the ceramic composition and type of filler. It is recommended to use 1.5 mm-thick ceramic materials for the fabrication of definitive full-coverage ceramic restorations, while veneers require 0.5 mm-thick materials. ALD is a promising CAD/CAM material that can be used for the fabrication of restorations with a proper strength in both anterior and posterior regions.