Running footwear is continuously being modified and improved; however, running-related overuse injury rates remain high. Nevertheless, novel manufacturing processes enable the production of individualized running shoes that can fit the individual needs of runners, with the potential to reduce injury risk. For this reason, it is essential to investigate functional groups of runners, a collective of runners who respond similarly to a footwear intervention. Therefore, the objective of this study was to develop a framework to identify functional groups based on their individual footwear response regarding injury-specific running-related risk factors for Achilles tendinopathy, Tibial stress fractures, Medial tibial stress syndrome, and Patellofemoral pain syndrome. In this work, we quantified the footwear response patterns of 73 female and male participants when running in three different footwear conditions using unsupervised learning (k-means clustering). For each functional group, we identified the footwear conditions minimizing the injury-specific risk factors. We described differences in the functional groups regarding their running style, anthropometric, footwear perception, and demographics. The results implied that most functional groups showed a tendency for a single footwear condition to reduce most biomechanical risk factors for a specific overuse injury. Functional groups often differed in their hip and pelvis kinematics as well as their subjective rating of the footwear conditions. The footwear intervention only partially affected biomechanical risk factors attributed to more proximal joints. Due to its adaptive nature, the framework could be applied to other footwear interventions or performance-related biomechanical variables.