The United States continues to endure the Opioid Overdose Crisis. Yet the burden of the crisis is not experienced uniformly across the United States. The discipline of geography offers a framework and spatial analysis methodology that are direct ways to investigate placed-based differences in opioid-related outcomes, exposures, and proxy measures. This dissertation combines the contemporary frameworks of health geography and geographic information science to provide novel studies on both the geographic patterns in opioid-related health measures at different scales across the United States as well as the actual spatial analytic methods that provide evidence on the Opioid Overdose Crisis. Three main research objectives are addressed over the course of the dissertation: 1) Model the space-time risk of heroin-, methadone-, and cocaine-involved emergency department visits in the greater Baltimore metropolitan area from January 2016 to December 2019 at the Zip Code Tabulation Area-level; 2) Estimate the local and neighboring relationship between prescription opioid volume and treatment admissions involving a prescription opioid across the United States from 2006 to 2014 at the county-level; and 3) Investigate and provide a framework as to how geographic information science has been used to provide knowledge over the duration of the crisis from 1999 to 2021. The first study demonstrates how a recently proposed spatio-temporal Bayesian model can produce disease risk surfaces for opioid-related health outcomes in data constrained scenarios. The second study executes spatial lag of X models on a nationwide prescription opioid distribution dataset, allowing for estimates on the relationship between neighboring prescription opioid volume and nonfatal treatment admissions involving a prescription opioid at the county-level. The third and final study of the dissertation developed and implemented a scoping review methodology, ultimately analyzing the study design and geographical elements of 231 peer-reviewed publications using geographic information science on research questions related to the crisis. Examination of the geographical components of these studies reveals a lack of evidence available at sub-state scales and in the Midwest, north Rocky Mountains, and non-continental United States. Several important future research directions - such as geographic meta-analyses and geographical machine learning - are identified. Taken as a whole, the dissertation provides a contemporary geographical framework to understand the ongoing United States Opioid Overdose Crisis.