pH-Sensitive hydrogels of 2-hydroxyethyl methacrylate/citraconic anhydride–modified collagen were obtained by free radical copolymerization/crosslinking in the presence of ammonium persulfate/N,N,N′,N′-tetramethylethylenediamine redox initiator system. Their pH-responsiveness was demonstrated by swelling behavior and ciprofloxacin release tests. Both unloaded and loaded hydrogels were characterized by Fourier transform infrared, scanning electron microscopy, and biocompatibility tests. The enzymatic degradation in the presence of Clostridium histolyticum mainly depends on initiator content. In vivo biocompatibility tests involving intraperitoneal hydrogels’ implantation in rats following the analysis by the granuloma test, leukocyte formula, immune parameters, and hepatic transaminases demonstrated their non-toxicity and biocompatibility with living tissues. The in vitro antimicrobial activity, in vivo biocompatibility, and in vitro biodegradability tests attest the possibility to use these new polymeric hydrogels with tailored properties as matrices for bioactive products in medical and pharmaceutical applications as wound care and targeting drug delivery systems. The ciprofloxacin release studies proved their potential as materials for wound dressings.