Objective <p>The objective of this study was to comprehensively analyze the therapeutic effects of combined oral nimesulide and sodium hyaluronate on inflammatory factors (metalloproteinase [MMP]-3, MMP-9, interleukin [IL]-1, and tumor necrosis factor [TNF]-α) and pain intensity in traumatic knee osteoarthritis (TKO).</p> Methods <p>A total of 100 patients with TKO were enrolled into an experimental (Exp) group (oral nimesulide sustained-release capsule + injection of sodium hyaluronate into the knee cavity) and a control (Ctrl) group (oral nimesulide sustained-release capsules), with 50 cases in each group. The visual analog scale (VAS) score, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores, inflammatory factors, quality of life and clinical efficacy were compared between the two groups.</p> Results <p>VAS and WOMAC scores of patients in the Exp group after treatment were greatly lower in contrast to those in the Ctrl group (<i>P</i> &lt; 0.05). Meanwhile, the levels of MMP-3, MMP-9, interleukin (IL)-1, and tumor necrosis factor α (TNF-α) in the joint fluid of patients in the Exp group after treatment were markedly lower and exhibited obvious difference with those in the Ctrl group (<i>P</i> &lt; 0.05). Additionally, the overall treatment effectiveness (OTE) in the Exp group was remarkably higher, which demonstrated a visible difference in comparison to the OTE in the Ctrl group (<i>P</i> &lt; 0.05). The Exp group exhibited significantly higher scores in physical function, social function, and mental health after 1, 2, and 3&#xa0;years of treatment compared to the Ctrl group. Additionally, the score for bodily pain was significantly lower in the Exp group than in the Ctrl group (<i>P</i> &lt; 0.05).</p> Conclusion <p>The combination of nimesulide and intra-articular injection of sodium hyaluronate effectively reduced pain intensity and the severity of arthritis in patients, thereby enhancing clinical efficacy.</p>