The United States (U.S.) is currently experiencing a substance use disorders (SUD) crisis with an unprecedented magnitude. The objective of this study was to recognize and characterize the most vulnerable populations at high risk of SUD mortality in the U.S., and to identify the locations where these vulnerable population are located. We obtained the most recent available mortality data for the U.S. population aged 15–84 (2005–2017) from the Centers for Diseases and Prevention (CDC). Our analysis focused on the unintentional substance poisoning to estimate SUD mortality. We computed health-related comorbidities and socioeconomic association with the SUD distribution. We identified the most affected populations and conducted a geographical clustering analysis to identify places with increased concentration of SUD related deaths. From 2005–2017, 463,717 SUD-related deaths occurred in the United States. White population was identified with the highest SUD death proportions. However, there was a surge of the SUD epidemic in the Black male population, with a sharp increase in the SUD-related death rate since 2014. We also found that an additional average day of mental distress might increase the relative risk of SUD-related mortality by 39%. The geographical distribution of the epidemic showed clustering in the West and Mid-west regions of the U.S. In conclusion, we found that the SUD epidemic in the U.S. is characterized by the emergence of several micro-epidemics of different intensities across demographic groups and locations within the country. The comprehensive description of the epidemic presented in this study could assist in the design and implementation of targeted policy interventions for addiction mitigation campaigns.