Medial tibial stress syndrome (MTSS) is a common injury in runners and military personnel. There is a lack of agreement on the aetiological factors contributing to MTSS, making treatment challenging and highlighting the importance of preventive efforts. Understanding the risk factors for MTSS is critical for developing preventive measures. The purpose of this systematic review and meta-analysis was to assess what factors put physically active individuals at risk to develop MTSS. Selected electronic databases were searched. Studies were included if they contained original research that investigated risk factors associated with MTSS, compared physically active individuals with MTSS and physically active individuals without MTSS, were in the English language and were full papers in peer-reviewed journals. Data on research design, study duration, participant selection, population, groups, MTSS diagnosis, investigated risk factors and risk factor definitions were extracted. The methodological quality of the studies was assessed. When the means and SDs of a particular risk factor were reported three or more times, that risk factor was included in the meta-analysis. There were 21 studies included in the systematic review and nine risk factors qualified for inclusion in the meta-analysis. Increased BMI (weighted mean difference (MD)=0.79, 95% CI 0.38 to 1.20, p<0.001), navicular drop (MD=1.19 mm, 95% CI 0.54 to 1.84, p<0.001), ankle plantarflexion range of motion (ROM; MD=5.94°, 95% CI 3.65 to 8.24, p<0.001) and hip external rotation ROM (MD=3.95°, 95% CI 1.78 to 6.13, p<0.001) were risk factors for MTSS. Dorsiflexion and quadriceps-angle were clearly not risk factors for MTSS. There is a need for high-quality, prospective studies using consistent methodology evaluating MTSS risk factors. Our findings suggest that interventions focused on addressing increased BMI, navicular drop, ankle plantarflexion ROM and hip external rotation ROM may be a good starting point for preventing and treating MTSS in physically active individuals such as runners and military personnel.