The development of effective treatment for the infection and bone defect resulting from advanced osteomyelitis is an urgent task in the orthopedic clinic. To simultaneously address the issues of infection and bone defect, the multifunctional electrospun scaffolds composed of polylactide (PLA), nano-hydroxyapatite-graft-polylactide (nHA-g-PLA), and antibiotic vancomycin (VAN) were developed for the treatment of advanced osteomyelitis in the present study. The composite scaffolds PLA/nHA/VAN could sustainably release VAN and exhibited excellent antibacterial activity toward S. aureus. The rough surface of PLA/nHA/VAN induced by the presence of nHA-g-PLA promoted the adhesion and proliferation of osteoblasts. More interestingly, PLA/nHA/VAN, especially PLA/nHA10/VAN8, reduced bone infections and boosted bone regeneration at the defect site with better outcomes than other treatment groups. In conclusion, it has been demonstrated to be highly effective for the treatment of osteomyelitis using the scaffolds with sustained release properties, which has great potential for real application in the orthopedic clinic.