With the aim to design bioactive dental restorative material, the present study investigated the influence of the antimicrobial agents chlorhexidine diacetate (CHX) and octinidine (di)hydrochloride (ODH) when incorporated in two different materials. Selected parameters were polymerization enthalpy, short-term drug release, and the effect on Streptococcus mutans as well as human gingival fibroblasts. Samples were made by mixing a nano-hybrid ormocer (O) and a methacrylate-based nano-hybrid composite (C), each with a mass fraction of 2% CHX or ODH. Release profiles and concentrations of active agents from the resins were assessed, and the cell proliferation of human gingival fibroblasts as well as Streptococcus mutans cultured with the eluates were evaluated. The influence on polymerization was assessed by means of differential scanning calorimetry. Both drugs, especially ODH, showed a decreasing effect on polymerization enthalpies associated with a lowered crosslinking degree. At the same time ODH appeared to be released more persistently than CHX. Moreover, ODH was more efficient with regard to bacteria growth inhibition but also more cytotoxic in terms of reduction of cell viability. ODH is deemed more appropriate for application in a dental resin-based drug delivery system, because of the more persistent drug release than seen for CHX.