This study aimed to determine the effectiveness of a single intra-articular injection of high-molecular-weight (HMW) hyaluronic acid (HA) at a dose of 4 mL/60 mg to reduce pain in people with knee osteoarthritis (OA) over 12 months. This retrospective study was conducted after obtaining ethical approval from Dhaka Medical College and Hospital, Bangladesh. From July 2020 to June 2021, a medical professional conducted the investigation. The investigation encompassed patients aged 40 to 70 hospitalized at our facility and diagnosed with Grade 2 or Grade 3 knee OAaccording to the Kellgren-Lawrence grading method. We divided the patients into two categories based on the treatments they received. Patients in Group A received a single injection of HMW HA (60 mg/4 mL) into the joint, along with instructions on activities of daily living, exercise, and painkillers. Group B patients received conservative therapy, which involved the use of nonsteroidal anti-inflammatory drugs (NSAIDs), muscle relaxants, therapeutic exercises, and a knee brace during physical activity. This study compared the efficacy of a single injection of HMW HA in the joint versus NSAIDs for managing OA-related symptoms over 12 weeks. The HA group initially scored similarly to the comparison group. By week three, however, the group receiving HA had considerably higher Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores (p=0.019). This pattern continued through weeks 6 (p=0.044), 9 (p=0.016), and 12 (p<0.001). Similarly, by week 3 (p=0.029), the visual analog scale (VAS) scores, which were initially identical (p=0.120), demonstrated a significant preference for HA, and this preference persisted through weeks 6, 9, and 12 (all p<0.001). The results show that by the third week, HA is more effective than NSAIDs at relieving pain and improving symptoms. The study's results indicated that over 12 weeks, the use of HMW HA led to statistically significant reductions in pain intensity, as measured by the VAS. Furthermore, HMW HA demonstrated a more significant improvement in WOMAC ratings, which assess physical function, stiffness, and pain, compared to NSAIDs. The findings suggest that administering HMW HA injections can significantly reduce symptoms and improve functionality in individuals with knee OA.