Osteoarthritis (OA) is the most common form of arthritis and a leading cause of disability worldwide. Current therapies include pain relief with oral uptake of non-steroidal anti-inflammatory drugs (NSAIDs) and intra-articular injections of hyaluronic acid (HA), to restore the lubricant and protective properties of the joint (viscosupplementation). The administration of both therapies is limited, especially for NSAIDs, given the systemic side-effects. This work intended to explore the potential of a novel injectable gel for osteoarthritis treatment consisting of hyaluronic acid (HA) combined with celecoxib (CEX) incorporated in a glycerol:sorbitol (GS)-based Low Transition Temperature Mixture (LTTM) for enhanced bioavailability. The efficacy of HA+GS+CEX versus HA, HA+CEX and saline control was tested in a post-traumatic osteoarthritis rat model (female Sprague-Dawley rats, n = 6 per group), induced by unilateral anterior cruciate ligament transection and partial medial meniscectomy (ACLt+pMMx). Outcome measures included knee edema, pain-associated behaviour, systemic CEX levels, bone changes as detected by micro-computed tomography, joint degeneration by Mankin score and synovitis by Krenn score. No changes were observed in knee edema between treatments. All HA-containing formulations effectively reduced synovitis, and alleviated pain-associated behaviour. HA+GS+CEX injection limited the peak CEX systemic exposure, prevented the loss of integrity of the subchondral bone plate, and inhibited cartilage degeneration. Overall, although all HA-based formulations reduced pain and inflammation, only the combination of HA+GS+CEX inhibited joint degeneration, suggesting an added therapeutic benefit over HA or HA+CEX alone.