Musculoskeletal infections (MSKI) have historically been a significant medical challenge. Only in recent years have effective treatments emerged due to advances in antibiotics, modern surgical techniques, and anesthesia. The current chapter focuses on improving patient outcomes and reducing diagnostic and treatment costs related to MSKI. Early identification and intervention are key. Factors contributing to high treatment costs, such as repeat surgeries and extended hospital stays, should be minimized. Management of MSKI begins with a thorough examination, laboratory tests, cultures, and imaging, followed by the use of appropriate antibiotics and, when necessary, surgical debridement. Advanced diagnostic tests, including unsedated magnetic resonance imagings and polymerase chain reaction (PCR) analysis, can enable faster, more accurate diagnoses and potentially reduce costs. However, despite these innovations, treating musculoskeletal infections remains both expensive and unpredictable.