Objective: A well-established link exists between obesity and knee osteoarthritis, and recent research has implicated diabetes mellitus as a potential cause of cartilage degeneration. The objective of this study was to use the National Health and Nutrition Examination Survey (NHANES) database to examine the association between knee pain and various metabolic factors. Methods: A retrospective cross-sectional study of the NHANES database from 1999 to 2004 was performed. The main outcome was any knee pain and bilateral knee pain. The main effects of interest were body mass index (BMI) and glycohemoglobin A1c. We additionally assessed various patient factors, including age, race, poverty, sex, and smoking status. Multivariable logistic regression models and interaction terms were analyzed. Results: Data on 12,900 patients were included. In the main adjusted analysis, the modifiable risk factors associated with any knee pain were overweight (odds ratio [OR] 0.91 [95% confidence interval (95% CI) 0.85–0.97), obesity (OR 1.54 [95% CI 1.42–1.66]), glycemic control (OR 1.20 [95% CI 1.03–1.38]), and current smoking (OR 1.15 [95% CI 1.05–1.27]) (all P < 0.05). These same factors remain significant for bilateral knee pain. Subgroup analysis showed that patients age <65 years have a 5% increase in the risk of any knee pain as their BMI increases, but patients age ≥65 years have a 10% increase in risk. Conclusion: This study confirms the association of knee pain with increased weight, glycemic control, current smoking, and age. Most of these risk factors can be modified in patients with knee pain and should be discussed when providing conservative treatment options.