Objective: Knee osteoarthritis is a common disabling chronic disease globally. Many pharmacological agents have been used efficiently in treatment of knee osteoarthritis. This study aims to evaluate metformin and serratiopeptidase together in treatment and stop of osteoarthritis progression by different mechanisms. Methods: Present study was a randomized clinical trial study conducted in Al-Kindi teaching hospital through the period from 1st January to 30th of May, 2017 on two groups of 80 osteoarthritis patients (group I; treated with metformin 850 mg oral tablets) and (group II; treated with metformin 850 mg oral tablets and serratiopeptidase 20 mg oral tablets). Parameters of two groups were compared with those of 40 normal healthy controls. Results: Patients in group II showed a highly significant reduction in pain scores post-treatment (p<0.001). Tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1ß) and interleukin 8 (IL-8) levels were significantly lowered among patients in group II treatment (p<0.001). Lower inflammatory parameters levels were observed among healthy controls and the parameters levels of group II patients were lower than those of group I patients. Conclusion: Metformin and serratiopeptidase regimen was efficient and safe in the treatment of knee osteoarthritis.