Background <p>Neonatal septic arthritis is an infection of the joint space with formation of purulent effusion within the joint capsule. It is an uncommon but serious condition with potentially devastating long-term complications if not diagnosed and managed promptly. The determinants of neonatal septic arthritis are not well documented in Ethiopia.</p> Objective <p>To identify determinants of septic arthritis among neonates admitted to Adama Comprehensive Specialized Hospital, Adama, Ethiopia, 2023.</p> Methods <p>Facility based unmatched case control study was conducted. Medical records of neonates admitted between September 1, 2019 and August 30, 2023 were reviewed. A total sample of 156 (78 cases and 78 controls) were included. Data were collected using a structured questionnaire through retrospective chart review. The data were entered into EPI-Info 7 and analyzed using SPSS version 21. Bivariate and multivariable logistic regression analyses were performed.</p> Results <p>In this study, the odds of having septic arthritis among premature neonates was about 10 times higher (AOR, 10.34, 95%CI = 1.74–61.21) compared to their counterpart. Moreover, neonates with hospital-acquired infection had more than four times higher odds of the septic arthritis (AOR, 4.57, 95%CI = 1.54–13.58) compared to those who did not have the hospital acquired infection.</p> Conclusion <p>Prematurity and hospital-acquired infection were independently associated with increased odds of neonatal septic arthritis. Strengthening infection prevention practices and quality care for premature neonates is recommended.</p>