Native joint septic arthritis (NJSA) is a severe, rapidly progressing joint infection, primarily bacterial, but also potentially fungal or viral. It causes synovial membrane inflammation and joint damage, requiring urgent and multidisciplinary management to prevent permanent joint damage and systemic sepsis. Common in large joints like knees, hips, shoulders, and elbows, NJSA is more prevalent in individuals with conditions such as rheumatoid arthritis, diabetes, immunosuppression, joint replacement history, or intravenous drug use. This review provides a comprehensive overview of NJSA, covering diagnosis, treatment, antibiotic therapy duration, surgical interventions, and the comparison between arthroscopic and open debridement approaches. It also explores the unique challenges of managing NJSA in patients who have undergone graft anterior cruciate ligament (ACL) reconstruction. The review discusses epidemiology, risk factors, pathogenesis, microbiology, clinical manifestations, diagnosis, differential diagnosis, antibiotic treatment, surgical intervention, prevention, and prophylaxis of NJSA, emphasizing the need for prompt diagnosis, aggressive treatment, and ongoing research to improve patient outcomes. Keywords include septic arthritis, joint infection, antibiotic therapy, arthroscopic debridement, open surgical debridement, ACL reconstruction, rheumatoid arthritis, diagnosis, microbiology. The review highlights the importance of early diagnosis and treatment, as well as the challenges in managing NJSA in patients with underlying inflammatory arthritis or those on immunosuppressive therapy. It also discusses the role of imaging, such as MRI and ultrasound, in diagnosing NJSA, and the importance of accurate microbiological identification for effective antibiotic therapy. The review emphasizes the need for tailored treatment approaches, including the use of appropriate antibiotics, surgical interventions, and postoperative care to prevent joint damage and systemic complications. It also addresses the challenges of managing NJSA in the context of graft ACL reconstruction, where the presence of the graft can complicate diagnosis and treatment. The review concludes with a discussion on the importance of ongoing research to improve diagnostic tools, treatment strategies, and preventive measures for NJSA.Native joint septic arthritis (NJSA) is a severe, rapidly progressing joint infection, primarily bacterial, but also potentially fungal or viral. It causes synovial membrane inflammation and joint damage, requiring urgent and multidisciplinary management to prevent permanent joint damage and systemic sepsis. Common in large joints like knees, hips, shoulders, and elbows, NJSA is more prevalent in individuals with conditions such as rheumatoid arthritis, diabetes, immunosuppression, joint replacement history, or intravenous drug use. This review provides a comprehensive overview of NJSA, covering diagnosis, treatment, antibiotic therapy duration, surgical interventions, and the comparison between arthroscopic and open debridement approaches. It also explores the unique challenges of managing NJSA in patients who have undergone graft anterior cruciate ligament (ACL) reconstruction. The review discusses epidemiology, risk factors, pathogenesis, microbiology, clinical manifestations, diagnosis, differential diagnosis, antibiotic treatment, surgical intervention, prevention, and prophylaxis of NJSA, emphasizing the need for prompt diagnosis, aggressive treatment, and ongoing research to improve patient outcomes. Keywords include septic arthritis, joint infection, antibiotic therapy, arthroscopic debridement, open surgical debridement, ACL reconstruction, rheumatoid arthritis, diagnosis, microbiology. The review highlights the importance of early diagnosis and treatment, as well as the challenges in managing NJSA in patients with underlying inflammatory arthritis or those on immunosuppressive therapy. It also discusses the role of imaging, such as MRI and ultrasound, in diagnosing NJSA, and the importance of accurate microbiological identification for effective antibiotic therapy. The review emphasizes the need for tailored treatment approaches, including the use of appropriate antibiotics, surgical interventions, and postoperative care to prevent joint damage and systemic complications. It also addresses the challenges of managing NJSA in the context of graft ACL reconstruction, where the presence of the graft can complicate diagnosis and treatment. The review concludes with a discussion on the importance of ongoing research to improve diagnostic tools, treatment strategies, and preventive measures for NJSA.