Background: The COVID-19 pandemic has worsened the opioid overdose crisis in the US. Rural communities have been disproportionately affected by opioid use and people who use drugs in these settings may be acutely vulnerable to pandemic-related disruptions due to high rates of poverty, social isolation, and pervasive resource limitations. Methods: We performed a mixed-methods study to assess the impact of the pandemic in a convenience sample of people who use drugs in rural Illinois. We conducted 50 surveys capturing demographics, drug availability, drug use, sharing practices, and mental health symptoms. In total, 19 qualitative interviews were performed to further explore COVID-19 knowledge, impact on personal and community life, drug acquisition and use, overdose, and protective substance use adaptations. Results: Drug use increased during the pandemic, including the use of fentanyl products such as gel encapsulated “beans” and “buttons”. Disruptions in supply, including the decreased availability of heroin, increased methamphetamine costs and a concomitant rise in local methamphetamine production, and possible fentanyl contamination of methamphetamine was reported. Participants reported increased drug use alone, experience and/or witness of overdose, depression, anxiety, and loneliness. Consistent access to harm reduction services, including naloxone and fentanyl test strips, was highlighted as a source of hope and community resiliency. Conclusions: The COVID-19 pandemic period was characterized by changing drug availability, increased overdose risk, and other drug-related harms faced by people who use drugs in rural areas. Our findings emphasize the importance of ensuring access to harm reduction services, including overdose prevention and drug checking for this vulnerable population.