Native joint septic arthritis (NJSA) is a severe and rapidly progressing joint infection, primarily bacterial but also potentially fungal or viral, characterized by synovial membrane inflammation and joint damage. It typically affects large joints like the knees, hips, shoulders, and elbows, with a higher incidence 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 its diagnosis, treatment, antibiotic therapy duration, and surgical interventions, including 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 highlights the need for prompt diagnosis, aggressive treatment, and ongoing research to enhance patient outcomes. Key aspects include epidemiology, risk factors, pathogenesis, microbiology, clinical manifestations, differential diagnosis, antibiotic treatment, surgical intervention, prevention, and prophylaxis.Native joint septic arthritis (NJSA) is a severe and rapidly progressing joint infection, primarily bacterial but also potentially fungal or viral, characterized by synovial membrane inflammation and joint damage. It typically affects large joints like the knees, hips, shoulders, and elbows, with a higher incidence 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 its diagnosis, treatment, antibiotic therapy duration, and surgical interventions, including 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 highlights the need for prompt diagnosis, aggressive treatment, and ongoing research to enhance patient outcomes. Key aspects include epidemiology, risk factors, pathogenesis, microbiology, clinical manifestations, differential diagnosis, antibiotic treatment, surgical intervention, prevention, and prophylaxis.