Metal-organic frameworks (MOFs) are microporous materials with high potential for biomedical applications. They are useful as drug delivery systems, antibacterials, and biosensors. Recently, composite materials comprised of polymer matrixes and MOFs have gained relevance in the biomedical field due to their high potential as materials to accelerate wound healing. In this work, we studied the potential applications of composite hydrogels containing MgMOF74, CaMOF74, and Zn(Atz)(Py). The composite hydrogels are biodegradable, being completely degraded after 15 days by the action of collagenase and papain. The composites showed high biocompatibility reaching cell viabilities up to 165.3 ± 8.6% and 112.3 ± 12.8% for porcine fibroblasts and human monocytes, respectively. The composites did not show hemolytic character and they showed antibacterial activity against Escherichia coli reaching up to 84 ± 5% of inhibition compared with amoxicillin (20 ppm). Further, the immunological assays revealed that the composites produce a favorable cell signaling stimulating the secretion of the TGF-β and MCP-1 cytokines and maintaining the secretion of TNF-α in normal levels. Finally, the composites showed potential to be used as controlled drug delivery systems reaching a release efficiency of 30.5 ± 2.5% for ketorolac. Finally, results revealed that ColGG-Zn(Atz)(Py) was the best formulation evaluated.