Interest in investigating minimalist footwear (MF) has grown exponentially in recent years. This article systematically reviews the benefits of MF for physical fitness, biomechanical factors, and injury incidence in middle and long distance runners. A systematic review of PubMed and FECYT (Web of Sciences, CCC, DIIDW, KJD, MEDLINE, RSCI, and SCIELO) was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines before 26 April of 2022. From the 583 studies initially found, 23 were included in the qualitative synthesis. The use of MF induces improvements in running economy and stride frequency in middle and long distance races and reduces the oscillations of a runner’s center of gravity and support time. From a biomechanical viewpoint, MF enhances forefoot support and increases knee stability, leading to greater foot and ankle mobility. In addition, MF reduces impact load at the knee joint.