OBJECTIVES: The objective of this study was to investigate the impact of COVID-19 on the mental health, substance use, and overdose concerns among people who use drugs (PWUDs) in rural communities to explore reasons for changes and ways to mitigate COVID-19 impact in the future. METHODS: We conducted semi-structured in-depth interviews with PWUDs in 5 rural Oregon counties with high overdose rates. Participants were identified through participant-driven sampling along with flyer and text advertising (n = 36). Research staff conducted audio-recorded in-depth interviews via telephone, assessing COVID-19 effects on substance use, mental health, and overdose risk. Transcribed interviewers were coded for themes using a semantic approach. RESULTS: Participants reported various mental health symptoms and experiences due to COVID-19, including increased feelings of boredom, loneliness, and depression; increased worry and stress; and increased suicidal ideation. Participants described varying impacts of COVID-19 on substance use. Overall, participants who used only methamphetamine reported decreased use and people who used only heroin or heroin with methamphetamine reported increased use. Most participants reported that they were not concerned about overdose and that COVID-19 did not impact their concerns about overdose, despite increases in risky use and suicidal ideations. CONCLUSIONS: As rural communities respond to the evolving impacts of COVID-19, there is increasing need to identify strategies to address PWUDs mental, physical, and social health needs during COVID-19.