Purpose <p>This study was conducted to assess the effect of Carbon Dioxide (CO₂) laser irradiation with different modes on the surface roughness (Ra) and shear bond strength (SBS) between multilayered zirconia and adhesive resin cement.</p> Methods <p>Sixty-three zirconia samples were randomly divided into three groups (<i>n</i> = 21) according to surface treatment protocols: sandblasting with 110&#xa0;μm alumina particles (S), CO₂ laser irradiation with 3 watts in continuous mode (CC) and CO₂ laser irradiation with 3.5 watts in pulsed mode (CP). Ra values were measured via atomic force microscope (AFM) and surface morphologies were examined under scanning electron microscopy (SEM). Adhesive resin cement was bonded onto zirconia after application of MDP-based primer. All samples were aged for 5000 thermo-cycles, subjected to shear load test until debonding then examined by stereomicroscope to identify the failure mode. Data were statistically analyzed via one-way ANOVA test (<i>p</i> &lt; 0.05).</p> Results <p>The highest Ra and SBS values were recorded in Group (S) followed by Group (CC) then Group (CP). There are statistically significant differences among the groups (<i>P</i> &lt; 0.05). The most common failure mode in all samples was mixed (adhesive-cohesive).</p> Conclusions <p>Sandblasting of multilayered zirconia markedly improves the bonding efficacy with adhesive resin cement compared to CO₂ laser irradiation, regardless the laser mode applied. Using CO₂ laser irradiation with continuous mode is preferred over the pulsed one for surface treatment of multilayered zirconia.</p>