Some evidence suggests that combining hyaluronic acid (HA) with platelet-rich-plasma (PRP) may offer synergistic benefits by enhancing the biological and mechanical properties of joints. However, data on the combination of HA+PRP vs. HA alone in the management of knee osteoarthritis (OA) remain limited. A double-blinded randomized controlled trial was conducted at an outpatient clinic and enrolled 58 patients with Kellgren-Lawrence grade 2-3 knee OA. They were randomly allocated to receive either intra-articular PRP combined with HA ( = 29 knees) or HA alone ( = 29 knees). The primary outcome was pain, assessed using a visual analog scale (VAS). Secondary outcomes included the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), health-related quality of life (EQ-5D-5L), and structural changes on MRI, measured by the Whole-Organ MRI Score (WORMS). The VAS, WOMAC, and EQ-5D-5L were evaluated at baseline and at months 1, 3, 6, and 12. MRI WORMS was assessed at baseline and 12 months. : The baseline characteristics were comparable between the HA+PRP and HA groups. Both interventions showed improvements in pain and function at 12 months. However, the between-group difference in VAS at 12 months-the primary outcome-was not statistically significant ( = 0.102) and did not exceed the minimal clinically important difference (MCID) of 20 mm. The HA group demonstrated significantly greater VAS score reductions at 1 month (-31.1 [95% CI: -38.9 to -23.2] vs. -14.3 [95% CI: -22.2 to -6.4], = 0.003) and at 6 months (-32.1 [95% CI: -40.1 to -24.1] vs. -19.2 [95% CI: -27.1 to -11.3], = 0.024), compared to the HA+PRP group, although these differences did not reach clinical significance. No significant between-group differences were observed in the WOMAC scores, EQ-5D-5L, or total WORMS scores at all time points ( > 0.05). At 12 months, MRI assessment revealed a significant decrease in bone marrow edema in the HA+PRP group (-0.7 [95% CI: -1.6 to 0.2]) compared to the HA group (0.7 [95% CI: -0.2 to 1.6], = 0.030). : Both HA+PRP and HA treatments were effective in reducing pain and improving function in patients with knee OA over 12 months. While HA demonstrated greater early pain relief, the addition of PRP was associated with a significant reduction in bone marrow edema at 12 months. These findings suggest potential structural benefits of HA+PRP, although clinical superiority over HA alone was not established.