Purpose: Prolonged durations of ischemia followed by reperfusion are known to cause irreversible injury to tissues and organs. The damage by ischemia/reperfusion (I/R) is characterized by proinflammatory responses as well as increases in intracellular Ca2+ and reactive oxygen species (ROS), which cause damage to the cell membrane, which may lead to cell death. Ischemic preconditioning (IPC) is known to reduce infarct size following prolonged durations of ischemia followed by reperfusion. Damages caused by I/R have similarities to exercise-induced muscle damage (EIMD) since both are characterized by inflammation as well as increases in intracellular Ca2+ and ROS Therefore, the purpose of this study was to investigate whether IPC reduces known markers of EIMD following eccentric exercise. Methods: Eleven healthy volunteers were stratified and randomized into two conditions (IPC and sham) in a crossover-design. Participants received an IPC (220 mmHg) or sham (20 mmHg) condition, consisting of 4x5 minute cuff inflations. The EIMD-protocol, consisting of 5 x 10 controlled eccentric contractions of the tibialis anterior (TA) muscle performed on a custom-built platform, was executed immediately following IPC/sham procedures. Muscle stiffness (using shear wave elastography), muscle thickness (using B-mode ultrasound), muscle strength (using maximal voluntary contraction test) and perceived pain (using numeric rating scale) were measured prior to IPC/sham procedures, immediately post-exercise as well as 24 and 48 hours post-exercise. Perceived pain was additionally assessed 72, 96, 120 and 144 hours post-exercise. Results: Perceived pain increased significantly between trials for both conditions, compared to baseline. Perceived pain did not significantly differ between the conditions (P > 0.05). Both conditions increased in perceived pain until 48 hours post-exercise (P = 0.005). However, only the sham condition increased perceived pain 72 hours post-exercise (P = 0.007). Muscle thickness increased significantly between trials 24 hours (P = 0.041) and 48 hours (P = 0.036) post exercise. However, muscle thickness did not differ between conditions (P = 0.734) and had no significant interaction (P = 0.851). No significant changes in muscle stiffness (P-values ≥ 0.471) and muscle strength (P-values ≥ 0.15) were found. Conclusion: The present findings indicate that IPC may reduce perceived pain following eccentric exercise of tibialis anterior (TA). No significant effects were observed in muscle stiffness, muscle swelling and muscle strength.