Background: Pain and fatigue are major clinical manifestations in patients with Ehlers-Danlos Syndrome (EDS). The aim of this study is to measure change of the effects of custom-made foot orthotics on some manifestations related to EDS, such as foot pain, foot functionality, fatigue, and quality of life. Methods: Thirty-six patients with EDS wore foot orthoses for three months. Foot pain, foot-related disability, foot functionality, fatigue, and quality of life were measured using the 11-point Numeric Rating Scale, the Manchester Foot Pain and Disability Index, the Foot Function Index, the Fatigue Severity Score, and the 12-Item Short Form Health Survey questionnaires, respectively, at the beginning and after 3 months. Results: Participants demonstrated significantly improved foot pain (p = 0.002), disability related to foot pain (p < 0.001), foot functionality (p = 0.001), fatigue (p < 0.007), and mental health-related quality of life (p = 0.016). The physical health-related quality of life did not show significant changes. Conclusions: The use of custom-made foot orthoses help in the management of the symptoms by participants. This study could contribute to the foot specialists being considered as an additional member in multidisciplinary teams that are trying to develop an approach for patients with EDS.