The aim of this in vitro study was to evaluate the effect of accelerated artificial aging (AAA) and fatigue on the biaxial flexural strength (BFS) of three types of monolithic high-translucency zirconia restorations compared with conventional low-translucency zirconia restorations. Four groups of 20 disc-shaped specimens (10 × 1.2 mm) were made from the following computer-aided design and computer-aided manufacturing (CAD/CAM) zirconia blocks: Low-translucency zirconia (Ceramill ZI-LT) as a control, and three brands of high-translucent zirconia (Lava Plus, Ceramill Zolid White, and Copran Monolithic HT). Ten discs from each group were subjected to the BFS test using the universal testing machine. The other 10 discs from each group were subjected to AAA (thermocycling, 3,500 cycles) and fatigue (250,000 cycles) before the fracture test. The definitive fracture load was recorded, and the BFS was calculated in accordance with International Organization for Standardization (ISO) 6872. The data were analyzed with one-way analysis of variance (ANOVA), Scheffe post hoc, and Mann-Whitney U test. Data analyses were evaluated at a significance level of p < 0.05. Significant differences were detected in the BFS among the four groups before AAA and fatigue. The mean BFS was highest with Ceramill ZI (935.3 ± 47.1 MPa), and least in Ceramill Zolid White (685.7 ± 32.6 MPa). After AAA and fatigue, significant differences were reported where the mean of BFS was highest with Copran Zr-i Monolithic HT (777.5 ± 21.2 MPa), and least in Ceramill Zolid White (576.0 ± 36.3 MPa). Furthermore, Mann-Whitney U test showed that AAA and fatigue significantly affect the BFS of each material individually. The AAA and fatigue significantly affected the BFS of the monolithic high-translucency zirconia restorations. Although monolithic high-translucency zirconia had significantly lower BFS than conventional zirconia tested in this study, they still have sufficient strength for clinical use.