Importance: Self-injury mortality (SIM) combines suicides and the preponderance of drug misuse-related overdose fatalities. Identifying social and environmental factors associated with SIM and suicide may inform etiologic understanding and intervention design. Objective: To identify factors associated with interstate SIM and suicide rate variation and to assess potential for differential suicide misclassification. Design, Setting, and Participants: This cross-sectional study used a partial panel time series with underlying cause-of-death data from 50 US states and the District of Columbia for 1999-2000, 2007-2008, 2013-2014 and 2018-2019. Applying data from the Centers for Disease Control and Prevention, SIM includes all suicides and the preponderance of unintentional and undetermined drug intoxication deaths, reflecting self-harm behaviors. Data were analyzed from February to June 2021. Exposures: Exposures included inequity, isolation, demographic characteristics, injury mechanism, health care access, and medicolegal death investigation system type. Main Outcomes and Measures: The main outcome, SIM, was assessed using unstandardized regression coefficients of interstate variation associations, identified by the least absolute shrinkage and selection operator; ratios of crude SIM to suicide rates per 100 000 population were assessed for potential differential suicide misclassification. Results: A total of 101 325 SIMs were identified, including 74 506 (73.5%) among males and 26 819 (26.5%) among females. SIM to suicide rate ratios trended upwards, with an accelerating increase in overdose fatalities classified as unintentional or undetermined (SIM to suicide rate ratio, 1999-2000: 1.39; 95% CI, 1.38-1.41; 2018-2019: 2.12; 95% CI, 2.11-2.14). Eight states recorded a SIM to suicide rate ratio less than 1.50 in 2018-2019 vs 39 states in 1999-2000. Northeastern states concentrated in the highest category (range, 2.10-6.00); only the West remained unrepresented. Least absolute shrinkage and selection operator identified 8 factors associated with the SIM rate in 2018-2019: centralized medical examiner system (β = 4.362), labor underutilization rate (β = 0.728), manufacturing employment (β = -0.056), homelessness rate (β = -0.125), percentage nonreligious (β = 0.041), non-Hispanic White race and ethnicity (β = 0.087), prescribed opioids for 30 days or more (β = 0.117), and percentage without health insurance (β = -0.013) and 5 factors associated with the suicide rate: percentage male (β = 1.046), military veteran (β = 0.747), rural (β = 0.031), firearm ownership (β = 0.030), and pain reliever misuse (β = 1.131). Conclusions and Relevance: These findings suggest that SIM rates were associated with modifiable, upstream factors. Although embedded in SIM, suicide unexpectedly deviated in proposed social and environmental determinants. Heterogeneity in medicolegal death investigation processes and data assurance needs further characterization, with the goal of providing the highest-quality reports for developing and tracking public health policies and practices.