Healing of intestinal chronic wounds remains a major challenge as current therapies are ineffective in promoting proper regeneration of the damaged intestinal wall. An innovative concept, based on a bioinspired multifunctional alginate-melanin hybrid 3D scaffold, to target both inflammatory and regenerative processes, is proposed herein. Hydrogel-entrapped melanin nanoparticles demonstrated free-radical scavenging activity, supported by the neutralization of free-radicals in solution (90%), and the in vitro capture of reactive oxygen species (ROS) produced by stimulated macrophages in an inflammatory-mimicking environment. Notably, scaffolds could be reused (at least 3 times), while maintaining these properties. The extracellular matrix (ECM)-inspired biomaterial, containing protease-sensitive and integrin-binding domains, exhibited remarkable ability for cell colonisation. Human intestinal fibroblasts and epithelial cells (Caco-2) co-seeded on lyophilized scaffolds were able to invade/colonize the construct and produce endogenous ECM, key for neo-tissue formation and re-epithelialization. Scaffolds presented tuneable mechanical properties and could be used both in hydrated and freeze-dried states, maintaining their performance upon rehydration, which are attractive features for clinical application. Collectively, our results highlight the potential of biofunctionalized alginate-melanin hybrid 3D scaffolds as multi-therapeutic patches for modulating inflammation and tissue regeneration in chronic intestinal wounds, which address a major but still unmet clinical need. The proposed multi-therapeutic strategy may potentially be extended to the treatment of other chronic wounds.