Multiple COVID-19 vaccines were proven to be safe and effective in curbing severe illness, but despite vaccine availability, vaccination rates were relatively low in the United States (U.S.). To better understand factors associated with low COVID-19 vaccine uptake in the U.S., our study provides a comprehensive, data-driven population-level statistical analysis at the county level. We find that political affiliation, as determined by the proportion of votes received by the Republican candidate in the 2020 presidential election, has the strongest association with our response variable, the percent of the population that received no COVID-19 vaccine. The next strongest association was median household income, which has a negative association. The percentage of Black people and the average number of vehicles per household are positively associated with the percent unvaccinated. In contrast, COVID-19 infection rate, percentage of Latinx people, postsecondary education percentage, median age, and prior non-COVID-19 childhood vaccination coverage are negatively associated with percent unvaccinated. Unlike previous studies, we do not find significant relationships between cable TV news viewership or Twitter misinformation variables with COVID-19 vaccine uptake. These results shed light on some factors that may impact vaccination choice in the U.S. and can be used to target specific populations for educational outreach and vaccine campaign strategies in efforts to increase vaccination uptake.