Advances in multi-level theory and statistical methods allow sound ecologic and multi-level analyses of the impact of structural factors on the syndemic. Studies of opioid misuse, overdoses, hepatitis C virus, and HIV demonstrate that area-level access to healthcare, medication-assisted treatment of opioid use disorders, sterile injection equipment, and overdose prevention with naloxone, as well as factors such as opioid marketing, income inequality, intensity of policing activities, and health care policies, are related to the prevalence of substance misuse, overdoses, infection risk, and morbidity. Structural variables can predict area-level vulnerability to the syndemic. The implementation of combined prevention and treatment interventions can control and reverse components of the syndemic. Recognizing and monitoring potent structural factors can facilitate the identification of areas at risk of vulnerability to the syndemic. Further, many structural factors are modifiable through intervention and policy to reduce structural vulnerability and create health-enabling environments. Evidence supports the immediate implementation of broader HCV and HIV testing and substance use screening, medication-assisted treatment, needle/syringe exchange programs, naloxone programs, increased population-level implementation of HCV treatment, and further attention to structural-level factors predicting, and contributing to, area-level vulnerability, such as degrees of opioid marketing, distribution, and prescribing.