This study aimed to evaluate and compare the mechanical properties of three CAD-CAM monolithic esthetic zirconia (Ceramill® Zolid FX Multilayer (ZF), IPS e.max® ZirCAD MT Multi (ZM), and KATANATM STML (KS)) with a CAD-CAM lithium disilicate glass-ceramic (IPS e.max® CAD LT (MC)) as control. 80 samples (20/group) were milled, sintered, and subjected to a three-point bending test (3-PBT) to measure flexural strength and elastic modulus; Vickers indentations were used to measure microhardness. The numerical outcomes were analyzed using one-way ANOVA with a statistical significance set at <0.05. Zirconia showed superior mechanical properties compared with lithium disilicate (P<0.05). ZM had the highest values of flexural strength (P<0.05), KS and ZM showed significantly higher elastic modulus values than ZF (P<0.05), and ZF and KS microhardness values were significantly higher than ZM (P<0.05). Monolithic multi-layered zirconia had enhanced mechanical properties when compared with lithium disilicate and can be a predictable replacement in clinical applications.