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Biomaterials have a vital role in the field of tissue engineering. In this study, we have developed a collagen hybrid scaffold comprising Annona reticulata fruit polysaccharide with a synergistic combination of Tetrahydrocurcumin (THC)-loaded ethyl cellulose (EC) microspheres with cinnamon bark extract as a cross-linking agent. Response Surface Methodology (RSM) was used to optimize the parameters for microwave-assisted extraction of polysaccharides from Annona reticulata. Further, the structural features of extracted polysaccharides were characterized by 13C CP/MAS NMR, LC-MS-MS, XRD, and TGA. The polysaccharide showed strong antioxidant activity analyzed by the DPPH method. The hybrid scaffold exhibits porous and interconnected morphology and shows better thermal stability due to strong interaction. The antimicrobial activity and sustained release of THC suggest that the hybrid scaffold could be an excellent biomaterial for antibacterial wound dressing applications.