An approximately 41-yr-old female Asian elephant (Elephas maximus) experiencing forelimb stiffness and decreased range of motion was diagnosed with bilateral carpal osteoarthritis (OA). Standing sedation combined with local anesthesia was used to deliver ultrasound-guided carpal articular injections of an autologous conditioned serum product, interleukin receptor antagonist protein, combined with hyaluronic acid. Within 2 mo of completing therapy, improved range and speed of motion were evident. Reduced inflammation was suggested by decreased carpal articular prostaglandin E2 levels. Subjectively improved clinical signs lasted approximately 5–6 mo, at which point carpal articular injections were repeated. Joint inflammatory markers were useful in gauging response to treatment and may provide guidance in the diagnostic and therapeutic approach to elephant OA. On the basis of the positive response noted, interarticular autologous therapy combined with hyaluronic acid should be considered for carpal OA in elephants.