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Background: Opioid-related overdose deaths have been increasing in the United States (U.S.) in the last twenty years, creating a public health challenge. Take-home naloxone is an effective strategy for preventing opioid-related overdose death, but its widespread use is particularly challenging in smaller cities, towns, and rural areas where it may be stigmatized and/or poorly understood. Methods: We analyzed data on knowledge and beliefs about drug use and naloxone among the general public in Nebraska, a largely rural state in the Great Plains region of the U.S., drawing on the 2020 Nebraska Annual Social Indicators Survey. Results: Respondents reported negative beliefs about people who use drugs (PWUD) and little knowledge of naloxone. Over half reported that members of their community view PWUD as blameworthy, untrustworthy, and dangerous. Approximately 31% reported being unaware of naloxone. Only 15% reported knowing where to obtain naloxone and less than a quarter reported knowing how to use it. Knowing where to obtain naloxone is associated with access to opioids and knowing someone who has recently overdosed, but having ever used opioids or being close to someone who uses opioids is not associated with naloxone knowledge. Finally, almost a quarter of respondents endorsed the belief that people who use opioids will use more if they have access to naloxone. Conclusion: Our findings highlight stigmatizing beliefs about PWUD and underscore the need for further education on naloxone as an effective strategy to reduce opioid-related overdose death. We highlight the implications of these findings for public education efforts tailored to non-urban communities.