Background—Mental health conditions and substance use are linked. During the COVID-19 pandemic, mental health conditions and substance use increased, while emergency department (ED) visits decreased in the U.S. There is limited information regarding how the pandemic has affected ED visits for patients with mental health conditions and substance use. Objectives—This study examined the changes in ED visits associated with more common and serious mental health conditions (suicidal ideation, suicide attempts, and schizophrenia) and more commonly used substances (opioids, cannabis, alcohol, and cigarettes) in Nevada during the COVID-19 pandemic in 2020 and 2021 compared with the pre-pandemic period. Methods—The Nevada State ED database from 2018 to 2021 was used (n = 4,185,416 ED visits). The 10th Revision of the International Classification of Diseases identified suicidal ideation, suicide attempts, schizophrenia, and the use of opioids, cannabis, alcohol, and cigarette smoking. Seven multivariable logistic regression models were developed for each of the conditions after adjusting for age, gender, race/ethnicity, and payer source. The reference year was set as 2018. Results—During both of the pandemic years (2020 and 2021), particularly in 2020, the odds of ED visits associated with suicidal ideation, suicide attempts, schizophrenia, cigarette smoking, and alcohol use were all significantly higher than those in 2018. Conclusions—Our findings indicate the impact of the pandemic on mental health- and substance use-associated ED visits and provide empirical evidence for policymakers to direct and develop decisive public health initiatives aimed at addressing mental health and substance use-associated health service utilization, especially during the early stages of large-scale public health emergencies, such as the COVID-19 pandemic.