Objective: Detection of the knee joint’s early osteoarthritis (OA) is important for its early management and prognosis; however, no reliable single biomarker is available for this purpose. This study aimed to determine the correlation between serum and synovial fluid calprotectin level in detecting early knee OA. Method: In a case-control study, serum and synovial fluid were collected from 283 patients with primary early OA knee and 50 healthy controls. Serum and synovial levels of calprotectin levels were measured using an enzyme-linked immunosorbent assay. Results: The mean serum calprotectin level was 3141 ± 2634 ng/mL in patients with OA knee and 607.08 ± 163.79 ng/mL in the healthy control group ([Formula: see text] [Formula: see text] 0.001). The mean synovial fluid calprotectin level was 626.1 ± 67.32 ng/mL in the study population and 424.98 ± 78.41 ng/mL in the control group ([Formula: see text] [Formula: see text] 0.05). Calprotectin levels were significantly higher in the early stages of OA knee. Conclusion: Serum calprotectin level correlates with the synovial fluid level. In the early OA knee, serum calprotectin level increases significantly and decreases afterward. However, the synovial fluid calprotectin level remains static or increases on the progression of the disease. Calprotectin may be used as a biochemical marker for early knee OA.