Osteomyelitis is a progressive disease characterized by damage to bone tissue by microorganisms through infectious and inflammatory processes. Local antibiotic applications have been used in chronic osteomyelitis and have been defined as an adjunctive treatment method.Biodegradable materials are also used for the same purpose by adding antibiotics. The fact that it does not require additional surgery to be removed is an important advantage. The current study is therefore intended to develop a biodegradable drug-loaded polymeric scaffold with good antibiotic release that can be an alternative to antibiotic-impregnated bone cement. Methods Tissue scaffold containing poly (2-hydroxyethyl methacrylate) (PHEMA) was prepared in our laboratory and loaded with Ertapenem and Daptomycin antibiotics. The surface morphology and pore geometries of drug-loaded and unloaded scaffolds were analyzed by SEM (scanning electron microscope) under vacuum. The dose-dependent antiproliferative effects of PHEMA scaffold, drug-loaded scaffold, cement, and drug-loaded cement on osteoblast cells were investigated. To evaluate drug release kinetics, the absorbance values of the scaffold loaded with Ertapenem and Daptomycin were measured with the spectrometer. For microbiological tests, Ertapenem and Daptomycin impregnated cement and scaffold, as well as the control scaffold and cement samples were investigated for their antibacterial activities on Staphylococcus aureusand Klebsiella pneumoniae strains using the disc diffusion method. Results The efficacy of antibiotic-impregnated scaffold and cement on both gram negative and gram positive microorganisms was investigated. Daptomycin zone diameter in S. aureus ATCC strain was 17 mm, whereas this value was 24 mm for scaffold and 22 mm for cement. Scaffold was found to be more effective than cement against S. aureus strain. On K. pneumoniae ATCC strain, it was found that this strain was resistant to Ertapenem, but the zone diameter was 21 mm for scaffold and 20 mm for cement.Ertapenem-loaded scaffold was found to be more effective than cement. It was found that the antimicrobial activity of the scaffold was higher than cement. When we evaluated the release profiles, for the Daptomycin-loaded cement group, 98%of Daptomycin was cumulatively released within 30 min and for the Daptomycin-loaded scaffold group, 100%of Daptomycin was cumulatively released in 6 days. To compare Ertapenem-loaded cement and scaffold, 98% of Ertapenem was cumulatively released within 10 min in the cement group. For the scaffold group, 100% of Ertapenem was cumulatively released in 17 days. We found that the scaffold released the antibiotic more slowly and during a longer duration. Therefore, it was thought that scaffold would be more effective on biofilm and treatment of osteomyelitis would be more successful. Conclusions The scaffold produced was compared with cement, and it was concluded that the scaffold has better release and antimicrobial efficacy.Scaffold is more advantageous than cement because it is bioeliminable. Thus, there will be no need for a second surgical intervention and possible mortality and morbidities will be prevented. Because of all these features, scaffold seems promising in the local treatment of osteomyelitis.