<p>The present study explores a hydrogel composite made of chitosan and carboxymethyl cellulose (CMC), designed for controlled antibiotic release with potential applications in transdermal drug delivery and fluorescent sensing. The hybrid hydrogel was synthesized by crosslinking fumaric acid to chitosan and CMC using free radical polymerization synthesis methodology. The synthesis of the hybrid hydrogel was optimized using RSM methodology. The synthesized hydrogel was characterized for swelling studies, chemical composition, surface morphology, hemocompatibility, cytocompatibility, controlled drug release properties and fluorescence characteristics. The hydrogel with good hemocompatibility and cytocompatibility swelled considerably to achieve a swelling ratio of 701.42% and 339.81% at pH values of 1.2 and 7.4, respectively. Amoxicillin was embedded within the hydrogel matrix to serve as a model antibiotic for release experiments. In vitro drug release studies revealed the sustained nature of the delivery and further its distinct dependence on pH and pore size. Chitosan-CMC matrix released 92.29% of amoxicillin at the end of 4 days with 75% more release at pH = 1.2 in comparison to pH = 7.4. The present system could effectively work as a highly pH sensitive drug release system. The performance of the present system in terms of its sustained release characteristics, excellent mechanical properties and good skin adhesion suggests its suitability for transdermal drug delivery. Moreover, the inherent fluorescence of the hydrogel due to aggregation induced emission facilitated its application in fluorescent sensing of amoxicillin in water. This study offers substantial evidence to support the potential of fumaric acid crosslinked chitosan-CMC hydrogel as a promising material for highly pH-sensitive controlled antibiotic delivery and fluorescent sensing.</p>