Melatonin, a natural hormone with antioxidant, anti-inflammatory, and regenerative properties, has gained increasing attention in tissue engineering for its ability to enhance the therapeutic potential of biopolymeric scaffolds. These scaffolds, designed to mimic the extracellular matrix, provide structural support and a bioactive environment for tissue regeneration. By integrating melatonin, researchers aim to create multifunctional scaffolds that promote cell proliferation, modulate inflammatory responses, and improve wound healing outcomes. Challenges in utilizing melatonin include maintaining its stability under light, heat, and oxygen exposure, and optimizing its release profile for sustained therapeutic effects. Innovative fabrication methods, such as electrospinning, 3D printing, and lyophilization, have enabled precise control over scaffold architecture and melatonin delivery. These techniques ensure enhanced interactions with target tissues and tailored regeneration processes. Combining melatonin with growth factors, cytokines, and antimicrobial agents offers the potential for multifunctional applications, from chronic wound management to bone and nerve regeneration. Continued research in this field promises transformative solutions in regenerative medicine, expanding the clinical applicability of melatonin-enriched scaffolds. This review highlights the current progress, challenges, and opportunities associated with harnessing melatonin's therapeutic potential within tissue engineering frameworks.