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Hindrance to successful therapy of colon cancer is generally characterized with reduced potency of a single drug at the active site of cancer, poor drug release, and most importantly, potential toxic side effects of the drug resulting in cytotoxicity. Therefore, we investigated combinatorial drug micelles which are a potent combination of twin anticancer drugs (indomethacin and piroxicam, IND+PIR mc) for successful therapeutics of colon cancer. The novel combinatorial micelles showed improved drug encapsulation efficiency, an in vitro burst release of the dual drugs, increased cytocompatibility and increased efficacy in tumor reduction (weight and volume) than in single drug micelles (IND mc or PIR mc). The improved IND+PIR MC were to have small size 150.36 ± 15.13 nm (to avoid being taken up by liver, lungs or kidney or to sediment) with poly dispersity index (PDI) value at 0.24 ± 0.01. The PDI values suggest homogenous distribution. Encapsulation efficiency of IND+PIR mc was calculated at 86%. IND+PR mc had improved biocompatibility as demonstrated by CRL‐1459™ (normal colon) cell line than IND mc or PIR mc individually. The in vivo studies in mice model clearly depict that subcutaneous tumor weight reduced by almost 75% and volume reduced drastically by 55% on administration of IND+PIR mc than IND mc or PIR mc. Furthermore, fewer side effects were found with IND+PIR mc. To conclude, IND+PIR mc may be a potential anticancer strategy to be explored more in the future. [ABSTRACT FROM AUTHOR]