Lifestyle is related to many chronic diseases, such as knee osteoarthritis (KOA). Food intake is important because it can be controlled. However, the causal relationship of food intake and KOA still remain unclear. To identify the relationship between food intake and KOA and to screen relevant targets. First, we performed two-sample Mendelian randomization (MR) analysis. A total of 16 kinds of food intake datasets were included, the inverse variance-weighted analysis showed that the KOA was negatively correlated with cereal intake (odds ratio (OR) 0.48; 95% CI 0.35–0.68; P = 1.98 × 10?5). Second, potential drug targets of KOA in plasma were explored, secreted protein acidic and rich in cysteine (SPARC, or osteonectin), SPARC, Cwcv, and Kazal-like domains proteoglycan 2 (SPOCK2) as the causal protein for plasma with KOA, and increased SPOCK2 (OR 0.84; 95% CI 0.77–0.92; P = 5.52 × 10?5), decreased the risk of KOA. Integrated transcriptomic analysis (P = 0.028 5) and in vivo (P = 0.039 5) showed consistent results. Finally, by metabolomics analysis and molecular docking, seven co-expressed small molecules were detected in cereal and were bound to SPOCK2. Our findings indicate the cereal intake was negatively correlated with KOA, and support the SPOCK2 as a novel potential target for cereal intake in KOA. Our study will provide a clinical dietary guidance for KOA patients and a theoretical basis for the development of novel, side-effect-free drugs for KOA.