The purpose of the present study was to (1) investigate the micro-shear bond strength and failure mode of a novel methacryloxydecyl-dihydrogen-phosphate (MDP) calcium-fluoride-releasing self-adhesive resin cement (TheraCem, BISCO) to a tooth structure (enamel and dentin) and to yttrium-stabilized zirconia after thermocycling, and to (2) compare the results with a universal non-MDP-containing self-adhesive resin cement (RelyX Unicem, 3M ESPE) as a control. Enamel and dentin specimens (20 discs each) were obtained by using a diamond saw (IsoMet 4000, Buehler) with copious water coolant. Twenty zirconia plates were obtained from IPS e.max ZirCAD blocks (Ivoclar Vivadent) and sintered in an inFire HTC speed high-temperature furnace (Dentsply Sirona). Resin-cement micro-cylinders were created on the bonded surface and filled with the tested cements (n = 10 for each surface/cement combination): Group A (control) used non-MDP-containing RelyX, whilegroup B (tested cement) used MDP-containing TheraCem MDP. Cements were left to self-cure for 5 minutes. All specimens were thermocycled for 5,000 cycles (THE-1100, SD Mechatronik). Micro-shear bond strength was measured using a universal testing machine, and debonded surfaces were examined for failure mode analysis with all morphologic and ultrastructure changes using a scanning electron microscope (Quanta 250 Field Emission Gun, FEI) attached with an energy dispersive x-ray (EDX) unit. The results were statistically analyzed. TheraCem had a slightly higher micro-shear bond strength (MPa) value than RelyX. Within enamel, TheraCem (6.46 ± 1.37 MPa) had a significantly higher mean μ-SBS value than RelyX (3.04 ± 0.99 MPa) (P = .002). Similarly, TheraCem in dentin (10.67 ± 1.27 MPa) had a significantly higher mean value than RelyX (6.46 ± 1.74 MPa) (P = .014). As for zirconia, TheraCem (39.76 ± 1.18 MPa) had a significantly higher mean μ-SBS value than RelyX (27.04 ± 1.92 MPa) (P < .001). Using MDP-containing calcium-fluoride-releasing self-adhesive resin cement (TheraCem) may improve bond strength to all tested substrates (enamel, dentin, and zirconia) and can be considered a promising cement for many clinicians. Further clinical studies are required to provide long-term clinical success data.