Purpose: To investigate the acute effect of repeated-sprint activity (RSA) on change-of-direction economy (assessed using shuttle running economy [SRE]) in soccer players and explore neuromuscular and cardiorespiratory characteristics that may modulate this effect. Methods: Eleven young elite male soccer players (18.5 [1.4] y old) were tested on 2 different days during a 2-week period in their preseason. On day 1, lower-body stiffness, power and force were assessed via countermovement jumps, followed by an incremental treadmill test to exhaustion to measure maximal aerobic capacity. On day 2, 2 SRE tests were performed before and after a repeated-sprint protocol with heart rate, minute ventilation, and blood lactate measured. Results: Pooled group analysis indicated no significant changes for SRE following RSA due to variability in individual responses, with a potentiation or impairment effect of up to 4.5% evident across soccer players. The SRE responses to RSA were significantly and largely correlated to players’ lower-body stiffness (r = .670; P = .024), and moderately (but not significantly) correlated to players’ force production (r = −.455; P = .237) and blood lactate after RSA (r = .327; P = .326). Conclusions: In summary, SRE response to RSA in elite male soccer players appears to be highly individual. Higher lower-body stiffness appears as a relevant physical contributor to preserve or improve SRE following RSA.