Background: The misuse of illicit substances is associated with increased morbidity and mortality; thus, substance abuse is a global health concern. However, a lack of laboratory-based research has limited the scientific assessment of drug misuse in the Arabian Gulf region. Thus, the primary aim of this study was to assess the problem of illicit drugs in Kuwait using laboratory-based analyses. Methods: We investigated the type and quantity of detained narcotic drugs and psychotropic substances from 2015 to 2018, number of abusers, and mortality among abusers. In total, 6220 cases from the Narcotic and Psychotropic Laboratory and 17,755 cases from the Forensic Toxicology Laboratory were reviewed and analyzed. Substances were identified and documented using gas chromatography–mass spectrometry and liquid chromatography–mass spectrometry. Results: Cannabis, including marijuana, was the most seized substance, followed by heroin, opium, and cocaine. Amphetamines, including methamphetamine, in the form of powder or pills, were seized in larger quantities than other psychoactive substances. Benzodiazepines, tramadol, Khat, synthetic cannabinoids, and psilocin were also seized. The most consumed substances were, in order, amphetamines (including methamphetamine), benzodiazepines, cannabis, and heroin. Drug misuse was considerably higher among men than among women. We report the death rate associated with the abuse of various illegal drugs according to sex. The mortality rate associated with single-drug use was the highest among abusers of heroin, benzodiazepines, and methamphetamine. The mortality rate asscoaited with multiple-drug use was the highest among abusers of heroin–benzodiazepines, cannabis–benzodiazepines, and cannabis–amphetamines. Conclusions: Our study shows the changing trends in quantity and variety of substances illegally abused and marketed in Kuwait. Additionally, we report a direct gender-based association between mortality and consumption of certain substances. These findings suggest that there is a growing need to conduct larger scale studies to implement new strategies, policies, and interventions in populations affected by illicit drugs.