Quaternary ammonium (QA) compounds have been widely studied as potential disinfectants in dental restorative materials. The present work investigates whether the gradual displacement of nanosilica by QA-clay nanoparticles may have an impact on the physicochemical and mechanical properties of dental nanocomposite resins. For this purpose, Bis-GMA/TEGDMA-based composite resins were initially synthesized by incorporating 3-(trimethoxysilyl)propyl methacrylate (γ-MPS)-modified nanosilica/QA-clay nanoparticles at 60/0, 55/5, 50/10, 40/20, and 30/30 wt% filler loadings. Their structural characterization was performed by means of scanning electron microscopy (SEM) and X-ray diffraction analysis (XRD). The degree of double bond conversion (DC) over time and the polymerization shrinkage were determined with Fourier transform infrared spectroscopy (FTIR) and a linear variable displacement transducer (LVDT), respectively. Mechanical properties as well as water sorption and solubility parameters were also evaluated after storage of nanocomposites in water for 7 days at 37 °C. Spectral data revealed intercalated clay configurations along with areas characterized by silica-clay clusters for clay loadings up to 30 wt%. Furthermore, the insertion of 10 wt% QA-clay enhanced the auto-acceleration effect also sustaining the ultimate (DC), reduced the setting contraction and solubility, and, finally, yielded flexural modulus and strength very close to those of the control nanocomposite resin. The acquired results could herald the advanced design of dental restorative materials appropriate for contemporary clinical applications.