In the design of chitosan-based drug delivery systems and implantable scaffolds, the biodegradation rate of the chitosan matrix represents a promising strategy for drug delivery and the function of carriers. In this study, we have investigated the degradation of chitosan with different degrees of N-acetylation, with respect to weight loss, water absorption, swelling behavior, molecular weight loss of bulk materials, and reducing sugar content in the media. Chitosan matrices were prepared by compression molding. The results revealed that the initial degradation rate, equilibrium water absorption, and swelling degree increased with decreasing degree of deacetylation (DD) and a dramatic rise began as DD of the chitosan matrix decreased to 62.4%. Chitosan matrices with DD of 52.6%, 56.1%, and 62.4% had the weight half-life of 9.8, 27.3, and more than 56 days, respectively, and the weight half-life of average molecular weight 8.4, 8.8, and 20.0 days, respectively. For chitosan matrices with DD of 71.7%, 81.7%, and 93.5%, both types of half-life exceeded 84 days because of the much slower degradation rate. The dimension of chitosan matrices during degradation was determined by the process of swelling and degradation. These findings may help to design chitosan-based biomedical materials with predetermined degradation timed from several days to months and proper swelling behaviors.