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Introduction: The immune system can produce various inflammatory mediators to protect the body from stress and surgical trauma. However, this excessive inflammatory response will interfere with the body’s immune system, causing systemic inflammatory response syndrome and multi-organ failure if allowed to continue [1]. Lidocaine as an anti-inflammatory is used to treat surgical pain and pain arising from the disease process and treat ventricular arrhythmias [2,3]. This study aims to prove the efficacy of systemic lidocaine injection as an anti-inflammatory drug in BALB/c mice with sterile musculoskeletal injuries. Methods: This study used a prospective experimental laboratory study on experimental animals of BALB/c mice using a simple randomized design. Sixteen adult white BALB/c mice (male, healthy, 10–12 weeks old, 35–40 g body weight, and no disability) were selected and randomly divided into two groups: the group given lidocaine (2 mg/kg body weight) and a group that was given sterile distilled water. NF-kβ and TNF-α protein levels were detected by ELISA, while mRNA expression of NF-kβ was analyzed and determined by quantitative real-time PCR. Results: Musculoskeletal injury significantly increased the expression of both mRNA and protein levels of NF-kβ and TNF-α protein level. In addition, the NF-kβ (protein and mRNA) and TNF-α (protein) levels in rats experiencing inflammation due to musculoskeletal injury were significantly decreased in the lidocaine group (p < 0.001). Conclusions: The administration of systemic lidocaine injection was able to inhibit the expression of mRNA NF-kβ, the protein levels of NF-kβ, and protein levels of TNF-α in mice with musculoskeletal injuries.Keywords: Lidocaine, mRNA expression, Protein levels, NF-kβ, TNF-α levels