To evaluate the effect of Nd:YAG laser irradiation as a prior desensitizing strategy on immediate and medium-term microtensile bond strength (µTBS) to simulated hypersensitive dentin. Flat mid-coronal dentin was obtained from third molars and submitted to a 600-grit SiC paper (1min; N: normal dentin) or subsequently challenged with citric acid (6%, 1min; H: simulated hypersensitive dentin). Afterwards, dentin was or was not (C: control; HC, NC - each n = 7) irradiated with Nd:YAG laser (L: laser; 1.0W/10Hz/100mJ/4 irradiations of 50-60s; HL, NL - each n = 7). A 2-step self-etch adhesive (Clearfil SE Bond) was applied and composite (Filtek Z350) buildups were constructed. After 24-h (distilled water/37°C) storage, specimens were sectioned into beams and tested (µTBS; 0.5mm/min) immediately or after 6-month aging. Three-way ANOVA and Tukey tests were applied (α = 0.05). Qualitative evaluation of the adhesive interface (n = 1 extra tooth per group) was performed by Confocal Laser Scanning Microscopy. Substrate condition (p < 0.001), laser irradiation (p < 0.001), and aging (p = 0.002) influenced the results. Furthermore, there was interaction between substrate and irradiation (p < 0.001). Laser irradiation favored µTBS exclusively to hypersensitive dentin immediately and after aging. µTBS to hypersensitive dentin was higher than that to the normal substrate only when it was laser-irradiated. In any case, immediate µTBS was always higher than that after aging. CLSM revealed longer and more numerous resin tags for simulated hypersensitive dentin, and shorter and fewer resin tags for laser-irradiated dentin. No differences were observed in the hybrid layer itself. Nd:YAG laser irradiation prior to restoration favored the µTBS of a self-etch adhesive and resin composite to hypersensitive dentin. Desensitizing strategies are usually tried before performing restorative treatments in hypersensitive dentin; therefore, they may influence behavior of the adhesive interface established. However, instead of causing concern, Nd:YAG laser irradiation revealed a favorable effect on the aforementioned interface.