Adipose-derived mesenchymal stem cells (AMDSCs) isolated from adipose tissue are stem cells with a multilineage differentiation potential, immune regulation function and highly self-renewal capacity. Compared with bone marrow mesenchymal stem cells (BMSCs), AMDSCs have some unique advantages, including abundant resource in adipose tissue, high extraction rate, and are easy to acquire tissue and so on. Hypoxic-ischemic encephalopathy (HIE) has very high mortality and disability rates, and the clinical therapeutic effect is not very satisfactory. ADMSC can decrease neurological deficits and improve neurological function following HIE through multiple mechanisms, including homing, paracrine, immune modulation, neural differentiation and endogenous neurogenesis, and the ADMSC constitute a promising therapy for HIE treatment. This review summarized the related mechanisms, clinical trials and questions about ADMSC treatment.