One of major challenges in orthopedics is chronic osteomyelitis infection. Systemic antibiotic therapy is required along with soft tissue and bone debridement in the therapy. The aim of this study was the preparation of biodegradable mesoporous silicon microparticles containing different antibiotics for chronic osteomyelitis produced by bacteria. To optimize the total yield, particle size, surface characteristics, pore size, loading capacity and in vitro release characteristics of the microparticles were demonstrated as well as stability assessment of drug under biological condition. Surface modification provides an efficient and reliable system for controlled release. Microbiological assay was performed using different bacterial strains. Different antibiotics loaded into silicon microparticles were characterized by energy-dispersive X-ray spectroscopy (SEM-EDS), and high performance liquid chromatography (HPLC). Antibiotic-loaded surface modified microparticles resulted to prolonging the release up to one month, depending on surface chemistry and pore sizes. The results of the microbiological assay show that the loading of antibiotics into microparticles is able to enhance the anti-bacterial activity of the drug significantly. These results persuade us to pursue attempts to simplify the management of bone infection without obvious intolerance to the patient.