Background: Osteoarthritis (OA) is a major cause of chronic pain and disability, and although NSAIDs (Non-steroidal anti-inflammatory drugs) remain central to its management, their long-term use is limited by gastrointestinal and cardiovascular risks. Polmacoxib, a novel COX-2 selective NSAID with additional carbonic anhydrase inhibitory activity, offers effective symptom relief with improved safety. Methods: This multicenter, retrospective observational study analyzed anonymized electronic health record data of 3,088 patients with OA treated with polmacoxib in routine clinical practice. Pain intensity was assessed on a standardized 0–100 scale at baseline and at 3 and/or 6 weeks. Safety was evaluated by documenting treatment-emergent adverse events, and paired statistical analyses were performed. Results: The mean patient age was 59.0 ± 12.0 years, with common comorbidities including hypertension (49.8%) and diabetes (36.9%). Polmacoxib significantly reduced pain scores from baseline at 3 weeks (mean change −43.7) and 6 weeks (mean change −42.6; p < 0.05). Adverse events related to treatment were uncommon and generally mild, comprising nausea (1.39%), vomiting (1.00%), abdominal pain (0.68%), headache (0.55%), and dizziness (0.39%). Conclusion: In real-world clinical practice, polmacoxib provided significant short-term pain relief with a favorable safety profile in patients with OA, including those with common comorbidities. These findings support its use as an effective and well-tolerated option for OA management.