The development of collagen hydrogels with tailored properties for improved applications in biomedicine represents an area of opportunity for materials science. The collagen can form semi‐interpenetrated networks (semi‐IPN) with various natural and/or synthetic polymers. This work aims the preparation of novel hydrogels generated from a collagen matrix cross‐linked with polyurethane (PU), and the subsequent inclusion of polysaccharide chains to form semi‐IPN systems with improved properties. The choice of polysaccharides for this purpose is related to their ability to modulate the biocompatibility and the antibacterial capacity in various biomedical strategies. The work contemplates to study the effect of the chemical structure of polysaccharide (hydroxyethylcellulose (HEC), hydroxypropylmethylcellulose (HPMC) or starch (Alm)) on the properties of these novel hydrogels. The results indicate that the semi‐IPN hydrogels that include Alm exhibit the formation of stronger intermolecular interactions promoted by hydrogen bonds than HEC and HPMC, significantly improving the mechanical properties and their degradation rate in acidic, alkaline, and proteolytic media; also showing high capacity to inhibit the growth of E. colli. The semi‐IPN hydrogels based on HEC and HPMC exhibit excellent improvement in both thermal and proteolytic degradation, compared with the collagen‐PU matrix. On the other hand, this semi‐IPN system does not present cytotoxic character for monocytes and fibroblasts growing for up to 48 h of culture. Therefore, these innovative 3D matrices will be excellent candidates with potential application in biomedical strategies such as wound healing dressings.