Chitosan is a natural polysaccharide that is mainly obtained from the shell of marine crustaceans including crabs, lobsters, shrimps, etc. Chitosan has been widely used in biomedicine due to its special characteristics of low toxicity, biocompatibility, biodegradation and low immunogenicity. However, owing to the limited solubility of CS in water, its water-soluble derivatives are preferred for the mentioned applications. Carboxymethyl chitosan (CMC) is one of the water-soluble derivatives of chitosan, which has antibacterial, anti-cancer, anti-tumor, anti-fungal, and antioxidant properties and is used in both drug delivery and enzyme delivery. This material is also utilized in tissue engineering, wound healing and bioimaging. For these reasons, in this article, different and novel methods by employing KI catalyst and/or ultrasonication are accomplished for the synthesis of valuable CMC.