INTRODUCTION: To better understand the development of the growing opioid crisis in the early 21st century, the authors studied trends in substance use disorder among 46,132,211 emergency department (ED) visit discharges in California between 2006 and 2011. METHODS: Utilizing the California State Emergency Department Database, the authors identified substance use based on International Classification of Diseases, Ninth Revision codes. Tabular and multivariable analysis methods were applied. ED visits were considered clustered at the level of patient. RESULTS: The authors observed a notable increase in substance use prevalence from 7.32 ± 6.07 to 12.21 ± 9.35 per 1000 ED visits. Nonopioid substance use was more prevalent among individuals aged ≤ 50 years old. Opioid use disorder (OUD) was associated with a higher mortality rate in the ED. In 2011, OUD was significantly higher among American Indians visiting the ED. A multivariable analysis revealed that OUD was an independent predictor for increased ED visits after controlling for demographic factors. DISCUSSION: Despite an overall decrease in mortality rate, opioid-related ED visits showed a higher mortality rate, underscoring the grave consequences of OUD. Nonopioid substance use was prevalent among younger age groups, suggesting a need for age-specific interventions. A major finding was the elevated OUD among American Indians, indicating persistent health disparities impacting this demographic. OUD was an independent risk factor for excess ED visits, which could strain health care systems. The authors suggest strategies like nonopioid pain management, community-level programs, and bridging ED with outpatient treatment facilities to mitigate the opioid crisis and ED overutilization. CONCLUSION: These findings advocate for tailored public health strategies, addressing the underlying disparities to combat the opioid epidemic effectively.