Background: Evidence regarding the performance-related effects of Actovegin is limited, despite legislated restrictions being in place for this supplement within sport settings. Objectives: Our study examined the effects of Actovegin on physiological responses and performance during maximal cardiopulmonary exercise in collegiate athletes. Methods: 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 (${\eta }_p^2$) were used to assess for between- and within-group differences. Results: A significant time * group effect (p = 0.036, ${\eta }_p^2$ = 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, ${\eta }_p^2$ = 0.893), peak minute ventilation (p = 0.004, ${\eta }_p^2$ = 0.456), ventilatory equivalents for carbon dioxide (p = 0.002, ${\eta }_p^2$ = 0.517), oxygen pulse (p = 0.006, ${\eta }_p^2$ = 0.434), VO₂ at first ventilatory threshold (p = 0.002, ${\eta }_p^2$ = 0.520), velocity at second ventilatory threshold (p < 0.001, ${\eta }_p^2$ = 0.997), VO₂ at second ventilatory threshold (p < 0.001, ${\eta }_p^2$ = 0.628), and peak velocity (p = 0.010, ${\eta }_p^2$ = 0.386), and a decrease in respiratory exchange ratio (p < 0.001, ${\eta }_p^2$ = 0.695). Conclusions: 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.