This study aimed to assess the safety and effectiveness of the highly cross-linked hyaluronic acid—LBSA0103—in patients with knee osteoarthritis (OA) as per the prescribing information (PI) in South Korea. A total of 3,140 subjects aged ≥19 years were enrolled in this post-marketing surveillance (PMS) study from 2013 to 2019. The subjects received one or two injections of LBSA0103. The median duration of follow-up was 308 days. Adverse events (AEs), adverse drug reactions (ADRs), and serious AEs (SAEs) were monitored. Effectiveness was evaluated based on an index of effectiveness in accordance with the guidelines established by the Ministry of Food and Drug Safety and using a 100-mm visual analog scale (VAS) for weight-bearing pain. Overall, 250 subjects (7.96%) experienced 292 AEs and of these, unexpected AEs occurred in 114 subjects (3.63% [95% CI: 3.00–4.35]). Injection site pain was the most frequent AE reported by 81 subjects (2.58% [95% confidence intervals (CI): 2.05–3.20]). One hundred subjects experienced 108 ADRs (3.18% [95% CI: 2.60, 3.86]) and 15 unexpected ADRs were experienced by 13 subjects (0.41% [95% CI: 0.22–0.71]). Seventeen subjects experienced 22 SAEs (0.54% [95% CI: 0.32–0.87]) during the entire PMS period, and all were considered “unlikely” related to the study drug. Most AEs were mild in terms of severity and resolved during the study period. LBSA0103 was also effective in relieving symptomatic pain in knee OA patients. The condition in more than 80% of the subjects was considered to be improved when assessed by the investigators. LBSA0103 resulted in a significant reduction in the mean VAS score at 12 weeks after the first and second injections (24.79 (± 20.55) mm and 17.63 (±12.31) mm, respectively;p<0.0001). In conclusion, LBSA0103, used for the treatment of knee OA in a real-world setting, was well tolerated, with an acceptable safety profile and consistent therapeutic effect.