Nutrition and health knowledge (NHK) is linked to people’s dietary behavior and health outcomes. However, studies on the associations between NHK and chronic diseases are limited. This study aimed to examine the association of NHK with five specific chronic diseases (diabetes/hyperglycemia, hypertension, dyslipidemia, coronary heart disease (CHD), and stroke) in central China. Individual NHK and disease status were investigated using a self-reporting questionnaire. We further added up the number of chronic diseases and used this as a secondary outcome. A total of 21,559 adults were enrolled in this cross-sectional study. NHK score was significantly inversely associated with diabetes/hyperglycemia, hypertension, CHD, and stroke (allp-trends < 0.001). Moreover, an inverse association was found between NHK and the number of chronic diseases, especially among responders with three or more chronic diseases. Stratified analyses showed that the above association was more likely to be stronger among younger, female, highly educated, and inner-city residents. However, NHK was negatively associated with dyslipidemia in less educated people and positively correlated with dyslipidemia in highly educated people. NHK showed an inverse relationship with specific chronic diseases and the number of chronic diseases. Improving NHK might be a key strategy for easing the global burden of chronic diseases.