The international, public health crisis caused by the rapid spread of SARS-CoV-2 has resulted in unforeseen medical and psychiatric consequences. We reviewed publications from January 2020 to January 2021, given that earlier documents were not relevant, to review findings on changes in substance use and overdoses during the pandemic. Additionally, this review of the literature also documents advocacy efforts, health service modification and challenges, as well as COVID-related health complications associated with substance use. Recent work focused on identifying changes in the distribution and use of substances as well as the unique challenges to promoting the health of persons who use substances in the current pandemic. Although COVID-19 has triggered unprecedented innovations in the organizational and public policy, the use of certain substances (alcohol, cannabis, cigarettes, fentanyl, heroin, and opiates) is increasing internationally. Unique associations between substance use and pandemic-related adverse health outcomes were identified. In addition, the pandemic precipitated significant barriers and disruptions to care. Given increased overdose rates and infections among people who use drugs, continued surveillance and vigilance are needed to assess changes and reduce use and adverse consequences during the continuing COVID-19 crisis. Changes are urgently needed to reduce adverse health outcomes because of treatment barriers and lack of adequate treatment options. Additionally, integrative approaches are necessary to promote the public health of persons who use substances. Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.