Both the repeated-bout effect and increased flexibility have been linked to reduced muscle damage, fatigue, and strength loss after intense eccentric exercise. Our purpose was to compare the eccentric-training (ECC) response after first priming the muscles with either static flexibility training or a single intense bout of eccentric exercise. Twenty-five participants were randomly assigned to flexibility training (n = 8; 3×/week; 30 min/day), a single bout of intense eccentric exercise (n = 9), or no intervention (control; n = 8) during a 4-week priming phase, prior to completing a subsequent 4-week period of eccentric training of the knee flexors. Testing was completed prior to the priming phase, before ECC, during acute ECC (0 h, 24 h, and 48 h after bouts 1 and 4), and after ECC. Measures included muscle thickness (MT; via ultrasound); isometric, concentric, and eccentric strength; muscle power (dynamometer); electromyography; range of motion; optimal angle of peak torque; and soreness (visual analog scale). Flexibility training and single-bout groups had 47% less soreness at 48 h after the first bout of ECC compared with control (p < 0.05). The flexibility training group had 10% less soreness at 48 h after the fourth ECC bout compared with both the single-bout and control groups (p < 0.05). Isometric strength loss was attenuated for the flexibility training group (−9%) after the fourth ECC bout compared with control (−19%; p < 0.05). All groups had similar increases in strength, MT, and power after ECC (p < 0.05). Prior flexibility training may be more effective than a single session of eccentric exercise in reducing adverse symptoms during the acute stages of eccentric training; however, these benefits did not translate into greater performance after training.