Simultaneously improving the strength and toughness of materials is a major challenge. Inorganic–polymer hybrids offer the potential to combine mechanical properties of a stiff inorganic glass with a flexible organic polymer. However, the toughening mechanism at the atomic scale remains largely unknown. Based on combined experimental and molecular dynamics simulation results, it was found that the deformation and fracture behavior of hybrids are governed by noncovalent intermolecular interactions between polymer and silica networks rather than the breakage of covalent bonds. Three methods were attempted to improve the balance between strength and toughness of hybrids, namely the total inorganic/organic (I/O) weight ratio, the size of silica nanoparticles, and the ratio of −C–O vs −C–C bonds in the polymer chains. Specifically, for a hybrid with matched silica size and I/O ratio, optimized mechanical properties were demonstrated in terms of strength (1.75 MPa at breakage), degree of elongation at the fracture point (31%), toughness (219 kPa), hardness (1.08 MPa), as well as Young’s modulus (3.0 MPa). It was demonstrated that this hybrid material shows excellent biocompatibility and ability to support cell attachment as well as proliferation. This supports the possible application of this material as a strong yet tough bone scaffold material.