This paper reports the structure-property relationship of novel biomedical hydrogels derived from collagen, water-soluble oligourethanes, and silica. The molecular weight (MW) of oligourethanes, synthesized from polyoxyethylene diol and hexamethylene, l-lysine, isophorone or trimethylhexamethylene diisocyanates (P(HDI), P(LDI), P(IPDI) and P(TMDI), respectively), is determined by the chemical structure of the starting aliphatic diisocyanate. Thus, the collagen polymerization process and both the characteristics and mechanics of the formed three-dimensional (3D) network had a direct relation with the oligourethane MW. The crosslinking of collagen with oligourethanes was compatible with orthosilicate polycondensation to deposit silica particles on the fibrillar 3D network. A higher crosslinking index was found in hydrogels formulated with P(HDI) and P(LDI) in comparison with P(TMDI) and P(IPDI). In spite of similar crosslinking extensions, P(LDI) induced an enhanced water uptake and enhanced susceptibility to degradation, contrary to the impact of P(HDI). Fibroblasts and macrophages cultured for 3 days on hydrogels formulated with P(LDI) showed a metabolic activity similar to collagen only hydrogels. However, we observed the highest cell metabolic activity on hydrogels formulated with P(LDI) after 7 day culture. After this time lapse, an enhanced secretion of chemoattractant cytokines transforming growth factor-beta1 (TGF-β1) and monocyte chemoattractant protein-1 (MCP-1 or CCL-2) was noted in macrophages cultured on hydrogels crosslinked with P(LDI). These tunable composite collagen hydrogels might be excellent candidates for holding and releasing bioactive molecules and nanomaterials intended to regulate cell behavior via their constituents and properties.