Objective To compare bonding of dental adhesive to hypomineralized enamel (HE) after pre-treatment with either 5% sodium hypochlorite (NaOCl) solution or papain-based papacarie gel. Methods Normal enamel (NE) and HE obtained from hypomineralized first permanent molars were acid-etched with 32% phosphoric acid and randomly allocated into no deproteinization, deproteinization using 5% NaOCl, or deproteinization usping papacarie gel groups. Subsequently, the specimens were bonded, packed with composite resins and subjected to micro-shear bond strength (MSBS) testing and the data analysed using 2-way ANOVA and Tukey tests. Furthermore, specimens from all groups were subjected for qualitative analysis using scanning electron microscope. Results Two way-ANOVA showed that the factor “enamel substrate” was significant (p < 0.001), “enamel pre-treatment” was not significant and interaction of the two factors was significant (p = 0.005). HE produced inferior bonding with dental adhesive compared to NE. Enamel pre-treatment with deproteinization agents enhanced bonding to HE. No significant difference in MSBS was evident between the two deproteinization agents (p > 0.05). Qualitative analysis of acid-etched moderate HE showed barely visible enamel rods with irregular etching pattern. Following acid etching and deproteinization, Type I and II etching patterns were observed in moderate HE; while a porous enamel surface with more profound etching patterns in severe HE. Conclusions Papain-based papacarie could be an alternative deproteinization agent for bonding dental adhesive to HE. Clinical significance Papain-based papacarie, a natural deproteinization agent and a proven chemo-mechanical caries removal agent could be an alternative to NaOCl for enhancement of bond durability of adhesive restorations to HE.