The design of hydrogels based on natural polymers that have modulation of antibacterial capacity, ideal performance in release capacity of encapsulated drugs, and desired bioactivity for applications in wound healing represents a modern trend in biomaterials. In this work, novel hydrogels of semi-interpenetrating polymeric networks (semi-IPN) based on collagen and xanthan gum were investigated. The linear chains of xanthan gum can semi-interpenetrate inside to matrix of crosslinked collagen with polyurethane under physiological conditions, generating amorphous surfaces with fibrillar-granular reliefs that have accelerated gelation time (about 15 min), super water absorption (up to 3100 %) and high inhibition capacity of pathogenic bacteria such as E. coli (up to 100 % compared to amoxicillin at 20 ppm). The increment of xanthan gum in the hydrogel (up to 20 wt.%) allows for improvement in the storage module, resistance to thermal degradation, slow the rate of hydrolytic and proteolytic degradation, allowing to encapsulate and controlled release of molecules such as ketorolac and methylene blue; besides, it shows to keep the metabolic activity of fibroblasts and monocytes at 48 h of evaluation, without observing cytotoxic effects. The bioactivity of these hydrogels is improved since they have excellent hemocompatibility and enhanced cell proliferation. Specifically, the hydrogel with 20 wt.% of xanthan gum shows to decrease the production of TNF-α and CCL-2 cytokines, increasing the production of TGF-β in human monocytes, which could be used to modulate inflammation and regenerative capacity in wound healing strategies.