Atopic dermatitis (AD) is a chronic skin inflammatory ailment commonly observed in young children and adults. Various therapeutic modalities are already explored for mitigation of AD but for prolong application very few modalities are recommended. Considering these challenges, we have successfully developed gliclazide-loaded hydrogels using the physical dispersion method. For preclinical assessment, we developed a DNCB induced an AD-like phenotype in mice, characterized by increased dermatitis index, scratching interval, ear thickness and weight, spleen and lymph node enlargement, mast cell infiltration, and elevated oxidative stress. However, topical application of the GLZ hydrogel significantly improved these DNCB-induced symptoms. Mice treated with the GLZ hydrogel exhibited a marked reduction in inflammatory markers in histological evaluations. Specifically, there was a decrease in epidermal thickness and mast cell infiltration compared to the DNCB + Vehicle group. Additionally, the topical GLZ hydrogel attenuated the AD-like phenotype by reducing oxidative stress markers. Importantly, these therapeutic effects occurred without significantly affecting blood glucose levels, highlighting the safety of the topical GLZ hydrogel. These findings demonstrate the potential of GLZ-loaded hydrogels as an effective and safe topical treatment for alleviating the symptoms of AD by targeting oxidative stress and inflammation.