This study evaluates the bond strength of four self‐etching adhesive systems with different acidity levels in normal and artificially hypermineralized dentin substrate. Healthy human molars were divided into groups: normal dentin—N (n = 36) and artificially hypermineralized dentin—H (n = 36). Self‐etching adhesive systems Clearfil S3 Bond (n = 9), Optibond All in One (n = 9), Clearfil SE Bond (n = 9), and Adhese (n = 9) were used for both the N and H groups. Transparent cylindrical matrices were positioned on the treated dentin surfaces, filled with composite resin, and light‐cured for 40 s. After the transparent cylindrical matrices were removed, the specimens were stored for 24 hr in a humid environment at 37°C and were subjected to a micro‐shear bond strength test. For each group, a specimen was prepared and evaluated in scanning electron microscope for adhesive interface observation. Normality was confirmed and the two‐way analysis of variance and Games–Howell post‐tests were conducted (α = .05). The data demonstrated an interaction between the adhesive system and type of dentin substrate (p < .01). For normal dentin, all adhesive systems assessed were adequate; however, in the hypermineralized dentin, the Clearfil SE Bond two‐step self‐etching adhesive system with mild pH presented the highest immediate bond strength. There was a predominance of adhesive failures for all adhesive systems in the different dentin substrates evaluated. It was concluded that the self‐etching adhesive systems evaluated were efficient for both substrates, and for the hypermineralized dentin, the Clearfil SE Bond presented a higher bond strength value.