The objective of this in vitro study was to investigate the effect of material type, resin cement type, surface treatment, and aging on the microshear bond strength (mu SBS) of self-adhesive resin cements (SARCs) to CAD/CAM blocks. CAD/CAM blocks (CeraSmart, CS; Lava Ultimate, LU; Shofu Block HC, HC; Vita Enamic, VE; Vitablocks Mark II, VM) were cut into 3-mm thick slices (96 specimens for each) and divided into groups: no treatment; 9% hydrofluoric acid etching; aluminum-oxide sandblasting; CoJet sandblasting. Following, the specimens were divided into three subgroups according to SARCs applied. Each specimen received four resin cement microtubules (n = 32 per subgroup). After 24 h, the cylinders of SARC were equally assigned into two groups (n = 16): immediate mu SBS testing and mu SBS testing after thermocycling. A shear force was applied to the adhesive interface through a mu SBS testing device. Additionally, specimens were analyzed with a contact profilometer and were evaluated with scanning electron microscopy. The data were analyzed using four-way ANOVA, p < 0.05. Material type, resin cement type, surface treatment, and aging influenced the mu SBS values (p < 0.001). A significant decrease in mu SBS was recorded for all groups after thermocycling. The most common failure mode was detected as an adhesive failure. The surface treatment and material type influenced the surface roughness with a significant interaction. Sandblasting was more successful for CS, LU, and HC, while HF etching was better for VE and VM. The use of MDP-containing SARCs would be advantageous for the zirconia-containing CAD/CAM materials (LU and HC).