Background Ventricular-arterial (VA) coupling is defined as the ratio between arterial elastance (EA) and left ventricular elastance (ELV). VA uncoupling, as occurs in hypertensive heart disease, is associated with adverse outcomes. This study sought to determine the relationship between American football (AF)-associated hypertension and VA uncoupling. Methods and Results This was a multicenter, longitudinal, and repeated measures observational study of collegiate AF athletes across 3 years of AF participation. Of 200 freshman athletes initially enrolled, 142 (67 Black [47%]/75 White [53%], 58 linemen [41%]/84 nonlinemen [59%]) were prospectively studied with echocardiography and applanation tonometry. Primary echocardiographic VA coupling outcome measures were EA/ELV and ΔEA/ELV, with increased EA/ELV indicating VA uncoupling. Adjusting for race and player position, AF athletes demonstrated increased EA/ELV (mean [95% CI]Δ, 0.10 [0.04-0.15]; P=0.001) and systolic blood pressure (SBP) (mean [95% CI]Δ, 11.4 [8.3-14.5] mm Hg, P<0.001) over their collegiate AF careers. In combination with longitudinal VA uncoupling, hypertension prevalence (including both stage 1 and 2) increased from 54% at baseline to 77% (44% stage 2) at the end of the study period (P<0.001). In multivariable mixed-effects linear regression analysis, higher SBP (β=0.021, P=0.02), lower E' (β=-0.010, P=0.03), and worse global longitudinal strain (β=0.036, P<0.001) were associated with higher EA/ELV. Increased SBP (ΔSBP, β=0.029, P=0.02) and worsened global longitudinal strain (Δglobal longitudinal strain, β=0.045, P<0.001) also predicted increased ΔEA/ELV. Conclusions VA uncoupling is associated with pathologically increased SBP and subclinical impairments in left ventricular systolic function in collegiate AF athletes, indicating a key mechanism underlying maladaptive cardiovascular phenotypes observed in this population. Future studies analyzing whether targeted clinical interventions improve VA coupling and health outcomes are warranted.