Background There are uncertainties regarding the diagnostic criteria, optimal treatment methods, interventions, monitoring and determination of remission of Charcot neuro-osteoarthropathy (CNO) of the foot and ankle in people with diabetes mellitus (DM). The aims of this systematic review are to investigate the evidence for the diagnosis and subsequent treatment, to clarify the objective methods for determining remission and to evaluate the evidence for the prevention of re-activation in people with CNO, DM and intact skin. Methods We performed a systematic review based on clinical questions in the following categories: Diagnosis, Treatment, Identification of Remission and Prevention of Re-Activation in people with CNO, DM and intact skin. Included controlled studies were assessed for methodological quality and key data from all studies were extracted. Results We identified 37 studies for inclusion in this systematic review. Fourteen retrospective and observational studies relevant to the diagnosis of active CNO with respect to clinical examination, imaging and blood laboratory tests in patients with DM and intact skin were included. We identified 18 studies relevant to the treatment of active CNO. These studies included those focused on offloading (total contact cast, removable/non-removable knee high devices), medical treatment and surgical treatment in the setting of active CNO. Five observational studies were identified regarding the identification of remission in patients who had been treated for active CNO. We did not identify any studies that met our inclusion criteria for the prevention of re-activation in patients with DM and intact skin who had been previously treated for active CNO and were in remission. Conclusions There is a paucity of high-quality data on the diagnosis, treatment, and prognosis of active CNO in people with DM and intact skin. Further research is warranted to address the issues surrounding this complex disease.