Background: Fatal drug overdose in the United States is a public health crisis fueled by increased opioid and polysubstance use. Few studies have compared the neighborhood-level socioeconomic characteristics associated with overdoses of various substance classes and, to our knowledge, no investigation has yet assessed these factors in relation to polysubstance overdoses. Further, no study has determined whether socioeconomic conditions predict other contextually relevant aspects of overdoses such as whether they occur at-home or out-of-home. Methods: Overdose data (2015–2018) were obtained from the Coroner/Medical Examiner's Office of Jefferson County, Alabama. The toxicology results of decedents with a known overdose locations (N = 768) were assessed for the presence of synthetic opioids, natural and semi-synthetic opioids, heroin, stimulants, benzodiazepines, and alcohol. Socioeconomic characteristics were obtained from the Unites States Census Bureau at the census tract level. Results: Stimulant overdoses occurred in neighborhoods with the highest rates of disadvantage relative to other substance and polysubstance overdose types. The majority of included overdoses occurred at-home (63.7%) and an index of socioeconomic disadvantage predicted overdose rates for both at-home and out-of-home overdoses. Heroin overdose deaths were more likely to occur at-home while polysubstance stimulant-heroin overdoses were more common out-of-home. Conclusions: An index of socioeconomic disadvantage was generally predictive of overdose, regardless of the setting in which the overdose occurred (in-home vs. out-of-home). The associations between neighborhood-level socioeconomic characteristics and fatal overdose can be tailored by substance type to create targeted interventions. Overdose setting may be an important consideration for future policy efforts, as overdoses were nearly twice as likely to occur at-home.