The main aim of this work is the synthesis and characterization of cross-linked chitosan systems. Chitosan hydrogels can be prepared by physical or chemical cross-linking of polymer chains. Chemical cross-linking, leading to the creation of hydrogel networks possessing improved mechanical properties and chemical stability, can be achieved using either synthetic agents or natural-based agents. In this work, the cross-linker Genipin, a naturally derived compound, was selected because of the lower acute toxicity compared to many other commonly used synthetic cross-linking reagents. In particular, the chemical stabilization of chitosan through genipin cross-linking molecules was performed and characterized by calorimetric analyses (differential scanning calorimetry), swelling measurements in different pHs, and ionic strength. The reaction kinetics was carried out by means of rheological measurements, and both the activation energy (Ea) and the reaction order (m) were calculated. The hydrogel analyses were carried out at different concentrations of genipin (GN1 and GN2). The results were used to evaluate the possibility to use the chemical cross-linked chitosan–genipin hydrogel for biomedical applications. © 2015 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2015, 132, 42256.