Background This study examined the effect of thermocycling on the flexural strength properties of four CAD/CAM ceramic materials at different thicknesses. Methods Four CAD/CAM ceramics of different types: advanced lithium disilicate (ALD), zirconia-reinforced lithium silicate (ZLS) lithium disilicate (LD), and leucite reinforced (LE), and at three varying thicknesses 0.5, 1.0 and 1.5 mm were examined. After subjecting all specimens to 5000 thermomechanical cycles, flexural strength was determined using a universal testing apparatus. Scanning electron microscopy (SEM) was employed for analysis. Two factorial ANOVA models assessed the association of different factors (ceramic type and thickness) with flexural strength and elastic modulus. The 95% confidence intervals (CIs) and adjusted means were computed. A p-value < 0.05 was designated significant. Results ZLS exhibited the highest flexural strength at 1.5 mm thickness, while LD showed the highest Young’s modulus of elasticity. The lowest flexural strength was observed in the 0.5 mm thickness group. There were notable variations in flexural strength across all ceramic materials, with the highest adjusted mean strength in the ZLS group, ALD, LD, and LE, respectively. Additionally, significant differences were noted in ceramic thickness, with 1.5 mm thickness showing the highest strength and 0.5 mm thickness the lowest. Conclusions Ceramic material thickness significantly impacts flexural strength, with 1.5 mm thickness deemed suitable for posterior restorations. Ceramic materials with zirconia fillers or matrix demonstrated higher flexural strength than other ceramics.