The objective of the present investigation was to synthesize soluble carboxymethyl-gellan gum (CMG) from gellan gum (GG) using statistical experimental design (DoE) strategy. Experimental design can potentially calculate the optimum reaction condition required to obtain response i.e. degree of substitution (DS) of CMG, which was statistically assessed. The effect of two process factors, namely concentration of monochoroacetic acid and water:isopropanol ratio on DS was investigated. Another objective of present study was to improve the mucoadhesive strength of optimized CMG by its covalent attachment with thiol moieties so as to get thiolated carboxymethyl-gellan gum (TCG). Synthesized CMG and TCG were characterized by FT-IR, DSC and NMR. Polymer compacts of TCG exhibited 3.73 fold greater adhesive strength on goat intestinal mucosa as compared with bare GG. In accordance with the promising results obtained; synthesized TCG can be considered as potential modified polymer for further drug delivery applications, especially mucoadhesive systems.