Despite the recommendations for COVID-19 preventive health behaviors, it continues to increase alarmingly. This study examined how media coverage, myths, political leaders, and community leaders influence the attitudes and misconceptions about COVID-19 and COVID-19 vaccination uptake in the Mississippi Delta region. This qualitative study employed focus group discussions (FDGs) with representatives from three rural counties in the Mississippi Delta. A thematic analysis approach was used for data analysis. Participants were aware of how COVID-19 is transmitted, the preventative measures that can be used to mitigate the spread of the virus, and misconceptions and beliefs that lingered in their communities. Participants were uncertain about the need for the COVID-19 vaccine in terms of perceived risks (e.g., side effects, efficacy, and safety) and its novelty. Participants also discussed a wide range of COVID-19 misinformation that resulted in distress and distrust of the vaccine and health behavior recommendations. There are varying misconceptions and beliefs about COVID-19 and COVID-19 vaccine among communities in the rural Mississippi Delta. Thus, multi-sectoral collaborations between agencies that can use risk communication frameworks to deliver accurate health information that can resolve misinformation about COVID-19 in rural communities are needed.