The present study aims at developing and characterizing gum odina ‐ sodium alginate based microsphere as a carrier for capecitabine. Microspheres with varying concentration of polymers (gum odina and sodium alginate) were formulated using calcium chloride as a cross‐linker by ionotropic gelation technique. The formulated microspheres were optimized by entrapment efficiency, drug yield, particle size, swelling index, and in vitro drug release study. The optimized microsphere (F6) was characterized in terms of SEM, AFM, FTIR, XRD, degradation study, moisture content study, and antioxidant activity. The F6 was spherical in shape with a mean diameter of 568.33 ± 45.76 μm and drug entrapment efficiency of 45.91 ± 2.94%. In vitro dissolution study of optimized formulation exhibited negligible released in 0.1 N HCl (pH 1.2) and followed by 100% release in phosphate buffer (pH 7.4) within 24 h. In vitro cytotoxicity assay (MTT) of formulation F6 on HT29 human colon cancer cell line indicated inhibition of the proliferation of tumor cell over a longer period of time. The overall experiment indicated that capecitabine loaded natural polymers based formulated microsphere could be a promising approach for the prevention of colon cancer.