To evaluate the flexural strength and Vickers microhardness of different CAD-CAM denture base materials. Sixty rectangular specimens (64 × 10 × 3.3 ± 0.2mm) were fabricated from 3 different denture base materials (G-CAM, Graphene-reinforced polymethylmethacrylate, GC), Ivotion Base (Prepolymerized polymethylmethacrylate, IV), and Denturetec (3D-printed resin, DT) either by using additive (DT) or subtractive manufacturing (IV and GC). Specimens of each group were divided into 2 subgroups (thermal cycled or nonthermal cycled, n = 10/group). Nonthermal cycled specimens were stored in distilled water at 37°C for 24 hours and subjected to 3-point flexural strength test with a universal testing machine. Thermal cycled specimens were initially evaluated for Vickers microhardness and subjected to thermal cycling (10,000 cycles at 5-55°C). Vickers microhardness values were remeasured, and the specimens were subjected to 3-point flexural strength test. Data were analyzed by using 2-way analysis of variance and Bonferroni-corrected Tukey honestly significant difference tests (α = 0.05). Material type and condition significantly affected flexural strength (p ≤ 0.004), whereas their interaction was nonsignificant (p = 0.778). Overall flexural strength of the materials in decreasing order was GC, IV, and DT (p < 0.001), regardless of the condition. Material had a higher effect on flexural strength (ηp2 = 0.731) than thermal cycling (ηp2 = 0.142). The effect of the interaction between the material type and thermal cycling on Vickers microhardness was significant (p < 0.001). GC had the highest microhardness before and after thermal cycling (p < 0.001). IV had higher microhardness than DT before thermal cycling (p < 0.001). However, DT and IV showed similar microhardness after thermal cycling (p = 0.665). Thermal cycling decreased the microhardness of GC and IV (p ≤ 0.022), whereas its effect on DT's microhardness was nonsignificant (p = 0.538). Material type had the highest effect on microhardness (ηp2 = 0.864) followed by the interaction between the main factors (ηp2 = 0.258). Graphene-reinforced polymethylmethacrylate had the highest flexural strength and Vickers microhardness values, regardless of thermal cycling. Thermal cycling reduced the flexural strength of all resins. Thermal cycling reduced the microhardness of milled polymethylmethacrylate, but not that of 3D-printed resin.