Background: Concussion in collegiate athletics is one of the most prevalent sport-related injuries in the United States, with recent studies suggesting persistent deficits in neuromuscular control after a concussion and an associated increase in risk of lower extremity injury. Purpose: To expand on the relationship between concussion and lower extremity injury by examining the effect of multiple concussions (MC) on rate and odds of future lower extremity injury in collegiate athletes after return to play (RTP) compared with matched controls. Study Design: Cohort study; Level of evidence, 3. Methods: From 2001 to 2016, 48 National Collegiate Athletic Association Division I athletes sustaining multiple concussions at a single institution were identified. Athletes with multiple concussions (MC) were matched directly to athletes with a single concussion (SC) and to athletes with no concussion history (NC) by sex, sport, position, and games played. Incidence of, time to, and location of lower extremity injury were recorded for each group after RTP from their first reported concussion until completion of their collegiate career. Logistic regression was used to analyze odds ratios (ORs) for sustaining lower extremity injury, whereas time to injury was summarized by use of Kaplan-Meier curves and log rank test analysis. Results: The incidence of lower extremity injury after RTP was significantly greater ( P = .049) in the MC cohort (36/48, 75%) than in SC athletes (25/48 = 52%) and NC athletes (27/48 = 56%). Similarly, odds of lower extremity injury were significantly greater in the MC cohort than in SC athletes (OR, 3.00; 95% CI, 1.26-7.12; P = .01) and NC athletes (OR, 1.66; 95% CI, 1.07-2.56; P = .02). Time to lower extremity injury was significantly shorter in the MC group compared with matched controls ( P = .01). No difference was found in odds of lower extremity injury or time to lower extremity injury between SC and NC athletes. Conclusion: Collegiate athletes with MC were more likely to sustain a lower extremity injury after RTP in a shorter time frame than were the matched SC and NC athletes. This may suggest the presence of a cohort more susceptible to neuromuscular deficits after concussion or more injury prone due to player behavior, and it may imply the need for more stringent RTP protocols for athletes experiencing MC.