Hybrid ionomer cements (HICs) are aesthetic polyelectrolyte cements that have been modified with a resin. The setting of HICs occurs by both monomer polymerization and an acid–base reaction. In addition, HICs contain a resin, which is substituted for water. Thus, the competition between the setting reactions and reduced water content inherently limits polysalt formation and, consequently the bioactive interactions. In this study, we explored the effects of polybetaine zwitterionic derivatives (mZMs) on the augmentation of the bioactive response of HICs. The polybetaines were homogenized into an HIC in different proportions (α, β, and γ) at 3% w/v. Following basic characterization, the bioactive response of human dental pulp stem cells (hDPSCs) was evaluated. The augmented release of the principal constituent ions (strontium, silica, and fluoride) from the HIC was observed with the addition of the mZMs. Modification with α-mZM elicited the most favorable bioactive response, namely, increased ion elution, in vitro calcium phosphate precipitation, and excellent biofouling resistance, which deterred the growth of the bridging species of Veillonella. Moreover, α-mZM resulted in a significant increase in the hDPSC response, as confirmed by a significant increase (p < 0.05) in alizarin red staining. The results of mRNA expression tests, performed using periodically refreshed media, showed increased and early peak expression levels for RUNX2, OCN, and OPN in the case of α-mZM. Based on the results of the in vitro experiments, it can be concluded that modification of HICs with polybetaine α-mZM can augment the overall biological response.