Topical formulations containing 5-Fluorouracil (5-FU) have been proven effective in preventing the proliferation of skin cancer cells. However, their use is linked to side effects such as inflammatory and allergic reactions. Dexamethasone (Dexa) is a synthetic glucocorticoid used across allergic reactions which can be useful in preventing the 5-FU side effects. This study aims to introduce 5-FU loaded deoxycholic acid micelles (DCA Mics) incorporated into carboxymethyl cellulose hydrogel matrix (CMC Hyd) containing Dexa to design Mic/Hyd based carriers cross-linked by physical and chemical cross-linker. The release of 5-FU and Dexa from the final formulation at pH of 5.5 was around 55 % after 5 h. The final formulation shows the pH-controlled release by crosslinking CMC Hyd, increasing the release of Dexa at physiological pH. The MTT results showed both Hyd and the synthesized Mics were non-toxic, but the toxicity increased significantly when 5-FU was incorporated into the formulation. 5-FU@Mic (IC50 = 5.5 μg/mL) was observed to be more potent cytotoxic against A431 compared to the free drugs 5-FU (IC50 = 17.5 μg/mL), and final formulation (IC50 = 26 μg/mL). The dual drug delivery systems might provide insights into the potential of pre-exposure of Dexa for mitigating inflammation caused by 5-FU.