Caffeine is widely used to enhance various types of exercise performance during competitions and training. However, results regarding the influence of caffeine supplementation on exercise-induced muscle damage (EIMD) have been inconsistent. This may be due to the conceptual confusion arising from the mixing of pre- and post-exercise caffeine supplementation in previous studies examining caffeine and EIMD. Given caffeine’s widespread use before exercise, this systematic review aimed to explore the influence of “pre-exercise” caffeine supplementation on EIMD and to provide concise insights into the issues with previous experiments. A systematic literature search from 3 databases was conducted to examine human studies investigating the effects of pre-exercise caffeine supplementation on EIMD. A total of 17 studies were included in this review. While 3 of the 17 studies reported an increase in creatine kinase (CK) immediately after exercise, the remaining studies did not report changes in CK activities between the caffeine/placebo groups/conditions. However, almost all of the included studies assessed EIMD by focusing on blood markers (almost exclusively CK) even though post-exercise CK activities are poor indicators of EIMD. These facts highlight the limited validity of previous results assessing the effects of pre-exercise caffeine supplementation on EIMD. Specifically, no study has assessed maximal voluntary torque, an appropriate EIMD marker, while accounting for the confounding ergogenic effects of caffeine itself. This systematic review revealed that the available data are insufficient to draw conclusions regarding the effects of pre-exercise caffeine supplementation on EIMD due to methodological limitations in the included studies.