Vaccines are one of the most successful tools for protecting the public’s health. However, widespread vaccine hesitancy in the Southern United States is preventing effective mitigation of the current COVID-19 pandemic. The purpose of this study was to assess COVID-19 vaccine acceptance among adults living in a largely rural Southern state. This cross-sectional study collected data from 1,164 Arkansas residents between October 3 and October 17, 2020 using random digit dialing. The primary outcome was a multidimensional COVID-19 vaccine acceptance measure with scores between -3 to +3. The full COVID-19 vaccine acceptance scale was measured along with perceived vaccine safety, effectiveness, acceptance, value, and legitimacy subscales. Statistical analyses were conducted using multivariable linear regression. Results indicated Black participants had the lowest overall vaccine acceptance (0.5) compared to White participants (1.2). Hispanic participants had the highest scores (1.4). In adjusted models, Black participants had 0.81 points lower acceptance than White participants, and Hispanic participants had 0.35 points higher acceptance. Hispanic participants had the highest scores for all five vaccine acceptance subscales, relatively equivalent to White participants. Black participants had consistently lower scores, especially perceived vaccine safety (mean -0.2, SD 0.1). In conclusion, the lowest vaccine acceptance rates were among Black participants particularly on perceived vaccine safety. While Black participants had the lowest acceptance scores, Hispanic participants had the highest. This variability shows the value of a multidimensional vaccine acceptance measure to inform COVID-19 vaccination campaign strategies.