INTRODUCTION: There is a noticeable lack of information on iatrogenic error (IE)-related deaths in the United States. To address this, we conducted a retrospective analysis examining temporal, regional, urbanization, and age-related trends in IE-related mortality from 1999 to 2020. METHODS: Utilizing the Centers for Disease Control and Prevention's Wide-ranging Online Data for Epidemiologic Research database, we identified crude and age-adjusted mortality rates (AAMR) per 100,000 persons. We calculated annual percentage changes (APCs) via the Joinpoint regression program. RESULTS: From 1999 to 2020, a total of 531,792 IE-related deaths were reported, with an overall decline in mortality rates. From 2015 to 2020, an increase in AAMR by an APC of 17.19% was noted. Similar trends were seen in the 65-85+ age group from 2015 to 2020 (18.39%). The largest percentage increase in death rates occurred in Noncore metropolitan areas. Significant disparities were observed among states, with mortality rates ranging from 4.45 of 100,000 in Massachusetts and 10.43 of 100,000 in Mississippi. Other states with high AAMR values include New Mexico and Wyoming. In addition, the West census region demonstrated the greatest increase in APC in mortality rates (APC: 25.36%) from 2015 to 2020 followed by the South, Midwest, and lastly Northeast regions. CONCLUSIONS: The data indicate a notable fluctuation in mortality rates over the years, underscoring the importance of targeted interventions to address the regional and age-specific disparities. Investigating the causes of mortality variations offers crucial opportunities to reduce IEs.