Background: Some studies investigated the relationship between musculoskeletal conditions and chronic diseases. However, no study examined the association between social determinants and chronic diseases among people at high risk for knee osteoarthritis. Thus, the current study was aimed to address this gap. Methods: A secondary data analysis was conducted on a total of 3280 men and women aged 45 to 79 who were recruited in the Osteoarthritis Initiative. Results: Multivariable logistic regression analyses show that age ≥ 65 years was associated with 1.98, 1.96, and 1.46 times odds of the presence of diabetes, heart attack, and multi-morbidity, respectively than age ≤ 64 years. Men were associated with 1.39, 1.41, 1.76, and 2.24 times odds of the presence of arthritis, cancer, diabetes, and heart attack, respectively than women. African American/Asian/ non-Caucasian was associated with 2.71, 2.56, and 1.93 times odds of the presence of arthritis, diabetes, and heart attack, respectively than Caucasian. Primary school/less education was associated with twice or more times the odds of arthritis and chronic obstructive pulmonary disease (COPD) than ≥high school education. Unemployment was associated with 1.41-, 1.73-, 1.58-, and 1.70-time odds of the presence of arthritis, cancer, COPD, and heart attack, respectively, then employed. Unmarried/widowed/ separated was associated with 1.41, 1.75, 2.77, 2.76, 1.86, and 3.34 times odds of the presence of arthritis, asthma, cancer, COPD, diabetes, and heart attack, respectively than married. Annual income < 50,000 was associated with 1.33-, 1.44-, and 1.38-time odds of the presence of arthritis, diabetes, and multi-morbidity, respectively, then annual income ≥50,000. Overweight/obese was associated with 2.28 times the odds of the presence of diabetes than healthy weight. Current/former smoker was associated with 1.57, 2.47, 2.53, 1.63, and 1.24 times odds of the presence of arthritis, cancer, COPD, heart attack, and multi-morbidity, respectively than a nonsmoker. Consuming alcohol was associated with 1.32-, 1.65-, 1.50-, and 1.24-time odds of the presence of arthritis, COPD, diabetes, and multi-morbidity, respectively, then nonalcoholic. Conclusions: Social determinants are associated with the presence of chronic diseases. Some of the social determinants are modifiable or treatable. Thus, these findings can inform public health strategies in the United States.