Methamphetamine (Meth) use and human immunodeficiency virus (HIV) infection are major public health problems in the world today. Ample evidence indicates that HIV transfection risk is greatly enhanced with Meth use. Studies have shown that both HIV infection and Meth abuse can cause neuronal injury leading to neurodegeneration. While many studies have focused on the individual effects of Meth and HIV on the brain, few investigations have been carried out on their co-morbid effect in the nervous system. In this review, we try to summarize recent progress on individual effects of Meth and HIV on neurodegeneration and their potential underlying mechanisms, in addition to exploring their co-morbid effect on the brain.