Background: May–Thurner syndrome (MTS) is an uncommon cause of deep vein thrombosis and unilateral lower extremity lymphedema. We present the largest case series to date of 26 MTS patients with lymphedema. We aim to report the pathophysiology of lymphedema in relation to venous dysfunction onset in MTS patients and evaluate the effectiveness of surgical lymphedema treatment. Methods: Retrospective case series. Patients treated for lymphedema with concurrent MTS diagnosis were retrospectively identified at a large academic medical center. Surgical interventions included lymphovenous anastomosis (LVA), vascularized lymph node transfer (VLNT), liposuction, and a combination of surgeries. Nonsurgical intervention included complete decongestive physical therapy (CDPT). Results: Twenty-six patients (19 female, seven male) were identified and had undergone prior iliac vein stenting. International Society of Lymphology (ISL) stage II–III patients underwent lymphatic surgery or CDPT, while stage I only underwent CDPT. Stage I patients demonstrated an average excess volume increase of 21.74% ± 23.11. In stage II, CDPT patients experienced a percent volume increase of 15.26% ± 11.06, while combination patients experienced a 102% ± 63.31 volume decrease. Stage III patients comprised CDPT, liposuction, VLNT, and combination; these groups and two of three VLNT patients demonstrated decreased limb volume percentage. Pre- and postoperative MRIs in surgically treated patients showed improved tissue bulk, edema reduction, and new lymphatic channel formation. Conclusions: Surgery was effective in reducing MTS-related lymphedema. The common co-occurrence of lymphedema and MTS presents an opportunity for screening, early intervention, and prospective studies.