To quantify the cross-sectional and longitudinal effects of hyperlipidemia on knee osteoarthritis (KOA), we studied 13,906 middle-aged or older participants from the Dongfeng-Tongji cohort. Physical examinations were performed at baseline and follow-up. Knee pain was diagnosed by self-reported pain or stiffness. Clinical KOA was diagnosed from knee pain complains and clinical X-ray radiographs. The prevalence of knee pain and clinical KOA was 39.0% and 6.7% at baseline, respectively. Hyperlipidemia was associated with knee pain (OR 1.34, 1.23-1.45) and clinical KOA (1.34, 1.15-1.55). Compared with the participants without hyperlipidemia or use of lipid-lowering drugs, those with hyperlipidemia but no use of lipid-lowering drugs had higher risks of knee pain (1.28, 1.15-1.43) and clinical KOA (1.20, 0.97-1.48), those with hyperlipidemia and use of lipid-lowering drugs had the highest risks of knee pain (1.40, 1.26-1.56) and clinical KOA (1.45, 1.21-1.75). The risks were not elevated among participants without hyperlipidemia but using lipid-lowering drugs for prevention of other diseases. Furthermore, each 1-unit increase in triglyceride was associated with 9% and 5% increases in the risk of clinical KOA prevalence and clinical KOA onset, respectively. In conclusion, hyperlipidemia is associated with elevated risks of knee pain and clinical KOA among middle-aged or older adults.