Background Low‐grade systemic inflammation is a relevant pathogenic mechanism underlying the development of hypertension. In this study, we hypothesized that plasma calprotectin levels, as a biomarker of neutrophil‐mediated inflammation, is associated with developing new‐onset hypertension in the general population. Methods and Results Plasma calprotectin levels were determined in 3524 participants who participated in the PREVEND (Prevention of Renal and Vascular End‐Stage Disease) study, a prospective population‐based cohort study. Plasma calprotectin levels were studied for associations with the risk of new‐onset hypertension, defined as systolic blood pressure of at least 140 mm Hg, diastolic blood pressure of at least 90 mm Hg, or the first recorded use of antihypertensives. Participants with hypertension at baseline were excluded. Median plasma calprotectin levels were 0.48 (0.34–0.66) mg/L, and median systolic blood pressure was 117 (109–126) mm Hg. Plasma calprotectin levels were significantly associated with the risk of new‐onset hypertension (hazard ratio [HR], per doubling 1.30 [95% CI, 1.21–1.41]; P <0.001), also after adjustment for age and sex (HR, 1.26 [95% CI, 1.16–1.37]; P <0.001), but not after additional adjustment for potentially confounding factors, including baseline systolic blood pressure (HR, 1.00 [95% CI, 0.90–1.11]; P =0.996). Stratified analyses showed significant effect modification by sex ( P _interaction =0.023) and urinary albumin excretion ( P _interaction =0.004), with higher HRs in men (compared with women) and in individuals with higher urinary albumin excretion (>9.3 mg per 24 hours) compared with lower urinary albumin excretion (≤9.3 mg per 24 hours). Conclusions Higher plasma calprotectin levels are associated with an increased risk of new‐onset hypertension in the general population. This association is dependent on baseline systolic blood pressure and is particularly prominent in men compared with women.