The present study reports on the long-term drug release and mechanical properties of bioactive dental filling materials based on chlorhexidine diacetate (CHX) or octinidine (di)hydrochloride (ODH) incorporated in a composite based on dimethacrylates or an ormocer. CHX or ODH were added to a nano-hybrid ormocer (O) and a nanohybrid composite (C) with the amount of 2 wt% to achieve four matrix-drug combinations: O-CHX, O-ODH, C-CHX, and C-ODH. Drug extraction and release were measured using high-performance liquid chromatography with diode-array detection (HPLC-DAD), while drug distribution was assessed by using energy dispersive X-ray spectroscopy (EDX). Drug release in water at 37˚C was observed over 87 d. To determine the material properties, the water absorption, water solubility, flexural strength and hardness were measured and compared to the reference materials. Persistent drug release over 87 d was observed for both ODH-based systems and both ormocer-systems, with the longest duration of activity seen for the O-ODH combination. Persistent drug release was achieved via the loosening of the polymer network indicated via decreasing polymerization enthalpies, enhanced water absorption, and water solubility. As a consequence, the flexural strengths of the materials were reduced. However, surface hardness was hardly reduced. ODH seems to be more adequate than CHX for the design of bioactive dental filling materials based on nanohybrid ormocer and composites.