Diabetes and depression are common comorbid conditions that impose a substantial health burden. Acupuncture may effectively improve symptoms in patients with diabetes and depression, but the underlying mechanism remains unclear. Brain-derived neurotrophic factor (BDNF) may play a vital role in the effects of acupuncture on diabetes and depression comorbidity. This review summarizes the potential role of BDNF in acupuncture for diabetes and depression comorbidity. BDNF appears to exert its effects via the BDNF-TrkB-ERK-CREB signaling pathway. BDNF levels are reduced in diabetes and depression, and acupuncture may increase BDNF expression, improving symptoms and glycemic control. High-quality research is needed to validate the efficacy of acupuncture for diabetes and depression comorbidity. Randomized controlled trials and mechanistic studies should investigate the BDNF pathway and other potential mechanisms. Improved understanding of the links between diabetes, depression and acupuncture may enable targeted and individualized patient care. Earlier diagnosis and management of diabetes and depression comorbidity should also be a priority.