To evaluate and compare the effect of two enzymatic chemo-mechanical caries removal agents with conventional caries removal using rotatory instruments on the adhesion of composite resin to dentin of permanent teeth. The sample comprised 30 permanent molars with caries lesions extending to the dentin, randomly distributed into three groups (n = 10 each): 1-Caries removal with rotary instruments (control group); 2-Caries removal with Papacárie Duo® (F&A Laboratório Farmacêutico, São Paulo, Brazil); 3-Caries removal with Brix 3000™ (Brix S.R.L., Carcarañá, Argentina). After caries removal, the specimens were rinsed and dried. Scotchbond Universal™ adhesive (3M, Saint Paul, Minnesota, USA) was actively applied in self-etch mode and light-cured. Resin composite increments were applied using a silicone mold (3 × 3 × 2mm) and light-cured. Shear bond strength (MPa), work-to-debonding (J/m2), and shear modulus (kPa) were evaluated. For statistical analysis, the level of significance was set at 5%. The control group presented significantly higher shear bond strength values (8.50 ± 2.69MPa) compared to the Brix 3000™ group (5.72 ± 1.55MPa, p = 0.008). There were no significant differences between Papacárie Duo® (6.66 ± 0.86MPa) and the other groups (p > 0.05). Regarding work-to-debonding, the Papacárie Duo® group had a significantly higher result (2944.41 ± 450.21J/m2) than the Brix 3000™ group (1189.41 ± 504.13J/m2, p < 0.001) and the control group (967.10 ± 270.01J/m2, p < 0.001). Concerning shear modulus, the control group showed a significantly higher result (558.67 ± 168.96kPa) than the Brix 3000™ group (339.79 ± 143.78kPa, p = 0.008) and the Papacárie Duo® group (223.04 ± 127.30kPa, p < 0.001). While the application of Papacárie Duo® did not negatively affect composite resin adhesion to dentin of permanent teeth, the application of Brix 3000™ reduced adhesive forces, potentially limiting its clinical use. Further investigations are warranted to elucidate the effects of these materials on dentin substrate, particularly through clinical studies.