Sinnott, AM, Krajewski, KT, LaGoy, AD, Beckner, ME, Proessl, F, Canino, MC, Nindl, BC, Turner, RL, Lovalekar, MT, Connaboy, C, and Flanagan, SD. Prevention of lower extremity musculoskeletal injuries in tactical and first responder populations: A systematic review and meta-analysis of randomized trials from 1955 to 2020. J Strength Cond Res 37(1): 239–252, 2023—Lower extremity musculoskeletal injuries (LEMSIs) impose a significant burden on tactical and first responder populations. To determine the effectiveness of LEMSI prevention strategies, we performed a systematic review and meta-analysis of randomized controlled trials published in English from 1955 to 2020 (PROSPERO: CRD42018081799). MEDLINE, EMBASE, Cochrane, CINAHL, ProQuest, and DTIC databases were searched for trials that assigned military service members, police, firefighters, or paramedics to LEMSI prevention interventions with a minimum surveillance period of 12 weeks. Evidence was synthesized as odds ratios (OR) for LEMSI occurrence between individuals assigned to interventions and those assigned to standard activities. Risk of bias was assessed with the Cochrane Risk of Bias tool 2.0. Random-effects meta-analyses were conducted for (a) physical training and (b) footwear modifications to reduce LEMSI and (c) footwear modifications to reduce stress fractures specifically. Certainty in the body of evidence was determined with the GRADE approach. Of 28,499 records, 18 trials comprised of more than 11,000 subjects were synthesized. Interventions included physical training (8, N = 6,838), footwear modifications (8, N = 3,792), nutritional supplementation (1, N = 324), and training modifications (1, N = 350). Overall risk of bias was generally moderate (N = 7 of 18) or high (N = 9 of 18). Physical training (OR = 0.87, 95% CI [0.71, 1.08], p = 0.22, I2 = 58.4%) and footwear modification (OR = 1.13, 95% CI [0.85, 1.49], p = 0.42, I2 = 0.0%) did not reduce LEMSI or stress fractures (OR = 0.76, 95% CI [0.45, 1.28], p = 0.30, I2 = 70.7%). Our results indicate that there is weak evidence to support current LEMSI prevention strategies. Future efforts will benefit from longer surveillance periods, assessment of women and nonmilitary populations, improved methodological rigor, and a greater breadth of approaches.