Osteomyelitis is a severe, progressive bone infection affecting approximately 21.8 per 100,000 individuals in the United States and remains a major challenge in orthopedic and reconstructive medicine. Staphylococcus aureus (S. aureus), responsible for nearly 75% of cases, is the most common causative pathogen. Current gold-standard management involves culture-directed antibiotic therapy administered for 4–6 weeks, often combined with surgical debridement and the use of antibiotic-loaded cement spacers. Despite these interventions, treatment frequently fails to achieve complete infection eradication, with recurrent or persistent disease reported in up to 40% of cases, contributing to chronic inflammation, impaired bone healing, and long-term functional deficits. These limitations highlight the need for therapeutic strategies that address infection control and bone regeneration. A narrative literature review was conducted to evaluate emerging tissue-engineered scaffold-based biomaterials as potential alternatives to conventional treatment. Emerging evidence suggests antimicrobial-loaded matrices, bioactive scaffolds, and stimuli-responsive biomaterials can provide localized drug delivery, structural support, and enhanced osteogenesis while improving infection control and osteointegration. Advances in targeted drug delivery, immunomodulatory biomaterials, and computational scaffold design further suggest opportunities for more effective therapies. These findings highlight the potential of scaffold-based biomaterials to improve osteomyelitis management, although further clinical studies are required.