Background: Cardiovascular diseases (CVDs) are a major public health concern. The impact of dietary components on CVD risk has been recognized, but their interactions require further investigation. This study aimed to examine the associations between major nutrient intake and CVD risk and to assess potential causal relationships via Mendelian randomization. Methods: We conducted a cross-sectional analysis using data from the National Health and Nutrition Examination Survey (NHANES) 2017–2020, with a sample size of 5464 adult participants. Nutrient intake was derived from two 24 h dietary recalls. Associations between four principal nutrients and CVD risk were evaluated via Mendelian randomization analysis. Additionally, weighted multivariable logistic regression analyses were performed to adjust for potential confounders, including age, sex, BMI, and other lifestyle factors. Results: An observational analysis revealed that increased log-transformed dietary fat intake was associated with reduced heart failure risk (OR = 0.722, 95% CI: 0.549–0.954). Log-transformed protein intake was protective against heart failure (OR = 0.645, 95% CI: 0.471–0.889), coronary artery disease (OR = 0.684, 95% CI: 0.504–0.931), and stroke (OR = 0.747, 95% CI: 0.568–0.988). IVW-MR analyses confirmed causal relationships between relative fat intake and heart failure risk (OR = 0.766, 95% CI: 0.598–0.982, p = 0.035) and between protein intake and stroke risk (OR = 0.993, 95% CI: 0.988–0.998, p = 0.010). MR analysis also revealed causal relationships between relative fat intake and coronary artery disease risk and between relative protein intake and hypertension risk. Conclusions: Both the observational and Mendelian randomization studies indicated that dietary fat is inversely associated with heart failure risk and that protein intake is correlated with reduced stroke risk. Future studies should investigate the optimal balance of macronutrients for CVD prevention, explore potential mechanisms underlying these associations, and consider long-term dietary interventions to validate these findings.
