Marathon running exerts physical stress and may lead to transient immune dysregulation, increasing susceptibility to airway inflammation and exercise-induced bronchoconstriction (EIB). This study investigated systemic levels of antimicrobial peptides in athletes and their association with EIB. Serum concentrations of angiogenin, human beta-defensin 2 (hBD-2), major basic protein (MBP), S100A8, and S100A8/A9 were measured in 34 marathoners and 36 half-marathoners at baseline, immediately after a race, and seven days postrace using enzyme-linked immunosorbent assays and compared with 30 sedentary controls. Lung function was assessed by spirometry to identify bronchoconstriction. Levels of hBD-2 and S100A8/A9 were significantly elevated postrace in runners compared to baseline and controls, returning to baseline during recovery. During recovery, S100A8 levels remained slightly elevated in marathoners with EIB. Similarly, human beta-defensin 2 was modestly increased in runners who developed bronchoconstriction. Notably, S100A8 levels correlated negatively with lung function parameters, including forced expiratory volume and mid-expiratory flows. These findings suggest that endurance running induces systemic inflammatory responses and modulates innate immune peptides, particularly in individuals prone to bronchoconstriction. These peptides may serve as biomarkers of respiratory stress and help guide personalized strategies in endurance sports.