Evidence regarding the performance-related effects of Actovegin is limited, despite legislated restrictions being in place for this supplement within sport settings. Our study examined the effects of Actovegin on physiological responses and performance during maximal cardiopulmonary exercise in collegiate athletes. A randomized, double-blind, placebo-controlled experimental design was adopted. Moderately trained collegiate athletes from various sports were randomly allocated to placebo (n = 8) or Actovegin (n = 8) groups. All athletes consumed three capsules across each day for seven days of loading. Athletes underwent two separate cardiopulmonary exercise tests one week apart. Separate 2 × 2 mixed ANOVAs and effect sizes (ηp2) were used to assess for between- and within-group differences. A significant time * group effect (p = 0.036, ηp2 = 0.278) was observed in systolic blood pressure. Significant main effects were only observed for time in several variables, with increases in peak oxygen uptake (VO2) (p < 0.001, ηp2 = 0.893), peak minute ventilation (p = 0.004, ηp2 = 0.456), ventilatory equivalents for carbon dioxide (p = 0.002, ηp2 = 0.517), oxygen pulse (p = 0.006, ηp2 = 0.434), VO2 at first ventilatory threshold (p = 0.002, ηp2 = 0.520), velocity at second ventilatory threshold (p < 0.001, ηp2 = 0.997), VO2 at second ventilatory threshold (p < 0.001, ηp2 = 0.628), and peak velocity (p = 0.010, ηp2 = 0.386), and a decrease in respiratory exchange ratio (p < 0.001, ηp2 = 0.695). Our findings suggest that although physiological and performance alterations were evident with Actovegin supplementation during cardiopulmonary exercise, no further benefits beyond those obtained with a placebo were attained.