Background: People who use drugs (PWUD) may be at an increased risk of experiencing negative effects related to COVID-19. Border and non-essential service closures may have placed PWUD at an increased risk of experiencing unintended consequences regarding drug consumption and supply patterns, as well as related outcomes. However, the extent of these effects upon this population is unknown. The current study examined how COVID-19 has impacted substance use supply and use characteristics among a national cohort of PWUD in Canada. Methods: We conducted semi-structured one-on-one telephone-based interviews with 200 adult PWUD across Canada who were currently using a licit or illicit psychoactive substance at least weekly, and/or currently receiving opioid agonist treatment (OAT). Thematic analyses were conducted using qualitative software. Results: PWUD attributed adverse changes to their substance use frequency, supply, use patterns, and risk behaviors and outcomes to COVID-19. Many participants noted supply disruptions with the majority indicating a decrease in potency and availability, and an increase in the price of substances since COVID-19. Nearly half of participants specified that they had increased their substance use, with some experiencing relapses. In terms of changes to risk level, many participants perceived they were at a greater risk for experiencing an overdose. Conclusion: This study demonstrated the impacts of COVID-19 on PWUD, including a significant disruption substance supply. For many, these changes led to increased use and substitution for toxic and adulterated substances, which ultimately amplified PWUD's risk for experiencing related harms, including overdoses. These findings warrant the need for improved supports and services, as well as accessibility of safe supply programs, take home naloxone kits, and novel approaches to ensure PWUD have the tools necessary to mitigate risk when using substances.