Osteomyelitis caused by drug-resistant pathogens is one of the most important medical challenges due to high rates of mortality and morbidity, and limited therapeutical options. The application of novel nano-scaffolds loaded with antibiotics has widely been studied and extensively evaluated for and inhibition of pathogens, regenerating damaged bone tissue, and increasing bone cell proliferation. The treatment of bone infections using the local osteogenic scaffolds loaded with antimicrobial agents may efficiently overcome the problems of the systemic use of antimicrobial agents and provide a controlled release and sufficient local levels of antibiotics in the infected sites. The present study reviewed various nano-scaffolds delivery systems of antimicrobial drugs evaluated to treat osteomyelitis. Nano-scaffolds offer promising approaches because they simulate natural tissue regeneration in terms of their mechanical, structural, and sometimes chemical properties. The potential of several nano-scaffolds prepared by natural polymers such as silk, collagen, gelatin, fibrinogen, chitosan, cellulose, hyaluronic, alginate, and synthetic compounds such as polylactic acid, polyglycolic acid, poly (lactic acid-co-glycolic acid), poly-ɛ-caprolactone have been studied for usage as drug delivery systems of antimicrobial agents to treat osteomyelitis. In addition to incorporated antimicrobial agents and the content of scaffolds, the physical and chemical characteristics of the prepared delivery systems are a determining factor in their effectiveness in treating osteomyelitis.