This study aims to evaluate the microstructural and mechanical properties of three commercial resin-based materials available for computer-aid design and manufacturing (CAD/CAM)-processed indirect dental restoration: Lava™ Ultimate Restorative (LU), 3M ESPE; Brilliant Crios (BC), COLTENE and Cerasmart™ (CS), GC Dental Product. The three types of resin-based composite CAD/CAM materials were physically and mechanically tested under two conditions: directly as received by the manufacturer (AR) and after storage under immersion in artificial saliva (AS) for 30 days. A global approximation to microstructure and mechanical behaviour was evaluated: density, hardness and nanohardness, nanoelastic modulus, flexural strength, fracture toughness, fracture surfaces, and microstructures and fractography. Moreover, their structural and chemical composition using X-ray fluorescence analysis (XRF) and field emission scanning electron microscopy (FESEM) were investigated. As a result, LU exhibited slightly higher mechanical properties, while the decrease of its mechanical performance after immersion in AS was doubled compared to BC and CS. Tests of pristine material showed 13 GPa elastic modulus, 150 MPa flexural strength, 1.0 MPa·m1/2 fracture toughness, and 1.0 GPa hardness for LU, 11.4 GPa elastic modulus; 140 MPa flexural strength, 1.1 MPa·m1/2 fracture toughness, and 0.8 GPa hardness for BC; and 8.3 GPa elastic modulus, 140 MPa flexural strength, 0.9 MPa·m1/2 fracture toughness, and 0.7 GPa hardness for CS. These values were significantly reduced after one month of immersion in saliva. The interpretation of the mechanical results could suggest, in general, a better behaviour of LU compared with the other two despite it having the coarsest microstructure of the three studied materials. The saliva effect in the three materials was critically relevant for clinical use and must be considered when choosing the best solution for the restoration to be used.