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The controlled release of diclofenac sodium (DFNa) from a chitosan-oxidized konjac glucomannan (CTS-OKG) polymer film was studied. Konjac glucomannan (KGM) was initially oxidized by sodium periodate and then cross-linked to CTS via imine bonds (–C=N–) to form the new CTS-OKG copolymer. The DFNa loaded CTS-OKG polymers were characterized by Fourier transformed infrared spectroscopy (FT-IR) and X-ray diffractometry (XRD). Finally, the release profiles of DFNa from the CTS-OKG polymer matrices were evaluated in a simulated gastrointestinal fluid system comprised of two hours in simulated gastric fluid (SGF; pH 1.2) followed by 24 h in simulated intestinal fluid (SIF; pH 7.4). A 1:2:1 (w/w/w) ratio of CTS:OKG:DFNa prepared at room temperature for 3 hours gave the highest % encapsulation efficiency (EE) of 95.6 ± 0.6 and resulted in a minimal release of DFNa ( < 1% over 2 h) in SGF (pH 1.2) and a significantly improved sustained release in SIF (pH 7.4) with ~6% and 19% release over 8 and 24 h, respectively), some 15- and five-fold lower than that of the two commercial DFNa preparations, Diclosian and Voltaren. This formulation may be used for further study as a long term intestine controlled release drug model (at least 3 days).