Substance use disorder is an emerging problem concerning to human health, causing severe side effects, including neurotoxicity. The use of illegal drugs and the misuse of prescription or over-the-counter drugs are growing in this century, being one of the major public health problems. Ethanol and cocaine are one of the most frequently used drugs and, according to the National Institute on Drug Abuse, their concurrent consumption is one of the major causes for emergency hospital room visits. These molecules act in the brain through different mechanisms, altering the nervous system function. Researchers have focused the attention not just in the mechanism of action of these drugs, but also in the mechanism by which they damage the nervous tissue (neurotoxicity). Therefore, the goal of the present review is to provide a global perspective about the mechanisms of the neurotoxicity of cocaine and ethanol.