Introduction The rapid increase in opioid-related deaths since the early 2000s is a major USpublic health concern. This crisis has transitioned from pharmaceuticals to illicit synthetic opioids and street mixtures. This epidemic has significantly impacted the Appalachian region. This study investigated opioid-related death rates among the Appalachian states, focusing on death rates among urban, suburban, and rural counties. Methods Opioid-related death data from 2018-2021 for the 13 states that make up the Appalachian region were collected using the Centers for Disease Control and Prevention Wide-ranging Online Data for Epidemiologic Research (CDC WONDER) database. Opioid analgesic overdose deaths were defined using ICD-10 codes X40-X44, X60-X64, and Y10-Y14, where an opioid analgesic was also coded (T40.2-T40.4). US census data was used to calculate opioid-related death rates by population. Counties were classified as urban, suburban, and rural using the 2013 Rural-Urban Continuum Codes from the US Department of Agriculture. The data were descriptively broken down and reported as either percentages or means. Results Of the opioid-related deaths between 2018 and 2021, 498 counties were identified in the 13 Appalachian states as having reported at least 10 opioid-related deaths per year. Among these counties, 337 (67.7%) were classified as urban/metropolitan, 138 (27.7%) as suburban, and 23 (4.62%) as rural. Overall, mean opioid-related deaths by populations per 1000 among all counties were 0.24 in 2018, 0.24 in 2019, 0.33 in 2020, and 0.38 in 2021. For urban/metropolitan counties, opioid-related deaths per 1000 gradually increased from 0.23 in 2018 to 0.35 in 2021. For suburban counties, the mean opioid-related deaths per 1000 increased from 0.25 in 2018 to 0.43 in 2021. For rural counties, the mean opioid-related deaths per 1000 increased from 0.43 in 2018 to 0.62 in 2021. Conclusion Opioid-related deaths, on average and by population, have risen steadily in the Appalachian region from 2018-2021 across all geographic areas (urban/metropolitan, suburban, rural). Rural counties consistently showed the highest opioid-related deaths per population compared to urban/metropolitan and suburban areas. Addressing social determinants of health such as income level, education level, healthcare access, and community-based interventions is crucial in combating this issue. Community and health system interventions must be implemented to combat the disproportionately high rate of opioid prescribing in the Appalachian region.