Background Experimental studies show that high‐sodium intake affects the innate immune system, among others with increased circulating granulocytes. Whether this relationship exists on a population level and whether this relates to disease outcomes is unclear. We aimed to test the hypotheses that (1) sodium intake is associated with granulocytes on a population level; (2) granulocytes are associated with the presence of hypertension and both cardiovascular and renal outcomes; and (3) the relation between high‐sodium intake and these outcomes is mediated by granulocytes. Methods and Results We performed an analysis in 13 804 participants from the prospective EPIC (European Prospective Investigation into Cancer)‐Norfolk cohort, with a mean age of 58 years and median follow‐up of 19.3 years. Analyses were carried out using calculated estimated sodium intake and sodium‐to‐potassium ratios from spot urines at baseline. The main outcomes were hypertension at baseline, and composite cardiovascular (mortality or cardiovascular events) and renal (mortality or renal events) outcomes during follow‐up. Sodium intake and urine sodium‐to‐potassium ratio were positively associated with circulating granulocyte concentrations after adjustment for confounders (β=0.03; P =0.028 and β=0.06; P <0.001, respectively). Granulocytes significantly mediated the associations of, respectively, sodium intake and urine sodium‐to‐potassium ratio with hypertension at baseline, and cardiovascular and renal outcomes. Conclusions Sodium intake is positively associated with circulating granulocyte concentrations, and higher granulocyte concentrations associate with worse long‐term cardiovascular and renal outcomes. Given the recently established immune‐modulating effects of sodium and the role of immune cells in both cardiovascular and renal disease, causality for this pathway may need consideration in further studies.