Over the last decades, new psychoactive substances (NPSs) have established a new pattern of drug synthesis and distribution. These compounds brought with them several challenges, including their analytical determination by known methodologies, the uncertainty of their toxicological effects, and the possible approaches used for control. In Brazil, the control of NPS started with a nominal list of proscribed compounds. But the variety of substances was so large that other strategies were implemented. Generic legislation was created as several groups began to emerge, such as phenethylamines, synthetic cathinones, and synthetic cannabinoids. The legislation also began to include salts and isomers of all listed substances and precursor chemical ingredients or plants that may be used to produce them. Those substances are known for the unpredictability of their effects, causing a wide range of symptoms, including seizures, aggression, and acute psychosis. Users under effect represent a high risk for themselves and others. In this study, we present an overview of the timeline in which NPSs were detected in Brazilian territory and the legislative approaches. A complete literature search was performed using PubMed, Scopus, the World Wide Web and Brazilian governmental websites employing relevant keywords such as NPS, legislation, and Brazil. Even with the high volume of legislative measures, the race against NPS intoxication cases and apprehensions continues to be fierce. There are limitations in the process of detection, identification, and prohibition of the substances in the country that demand a multifactorial approach, stronger public health measures, scientific research, as well as harm reduction strategies. Nevertheless, the Brazilian scenario on NPS arrival reflects a worldwide problem faced by many countries. In conclusion, it is stated that the use of multiple legislative strategies such as prohibition lists and generic controls can provide for better regulation of the NPS problem. However, this issue needs to be addressed by multiple organizations, including police departments and the public health system, and that effort needs to be coordinated and standardized for all Brazilian Federal states.