OBJECTIVE: Osteoarthritis (OA) is a prevalent and disabling joint condition that affects millions worldwide, particularly in the knee joint, and it presents limited therapeutic options. Platelet-rich plasma (PRP) and hyaluronic acid (HA) have emerged as promising intra-articular treatments. This study aimed to compare the effects of single-dose PRP and HA on pain, functionality, and stiffness in patients with knee OA over a 12-week follow-up period. METHODS: A retrospective analysis was conducted on 64 patients who underwent single-dose intra-articular HA or PRP treatment for knee OA between December 2021 and June 2022. Pain and functional outcomes were assessed using the Visual Analogue Scale (VAS) and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores. Patient satisfaction was evaluated using a Likert scale. Appropriate statistical analyses were performed to compare treatment outcomes and p<0.05 was considered statistically significant. RESULTS: Both PRP and HA treatments led to significant improvements in pain, functionality, and stiffness over the 12-week follow-up period. VAS pain scores decreased significantly in both groups, but a greater reduction was observed in the HA group. Additionally, the HA group exhibited superior improvement in the WOMAC physical function score at the 4-week mark (p=0.047). CONCLUSION: This study is another novel contribution to the growing literature on treatment of PRP and HA treatments for knee OA, where we highlighted the potential benefits of single-dose HA in alleviating pain and enhancing physical function.