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Background/Objectives: The implementation of COVID-19 vaccination in the United States has revealed substantial disparities driven by geography, socioeconomic conditions, and political ideology. This study examines the association between these factors and COVID-19 vaccination uptake across 360 counties in four U.S.–Mexico border states, characterized by distinct socio-political traits. Methods: Using county-level data, this study employed multivariable regression analysis and GIS mapping to assess the effects of income, education, employment, age, race, ethnicity, occupation, metropolitan status, border status, and political affiliation on Dose 1, Dose 2, and booster vaccination rates. Results: The analysis showed that Dose 1 vaccination rates were significantly higher in border counties and metropolitan areas. Democratic population share and per capita income were positively associated with vaccination uptake. Dose 2 vaccination rates exhibited patterns similar to those observed for Dose 1. Booster vaccination rates were positively associated with Democratic affiliation, the proportion of the population with at least a high school education, and the share of individuals aged 65 years and older. In contrast, unemployment rates were negatively associated with booster uptake. Racial and ethnic composition was also associated with vaccination outcomes: higher Black population shares were associated with lower Dose 1 vaccination rates, whereas higher Native American population shares were associated with higher vaccination rates. Booster uptake was higher with larger shares of the Asian population but slightly lower with larger shares of the White population. Conclusions: COVID-19 vaccination uptake in U.S.–Mexico border counties was associated with a complex interaction of geographic, socioeconomic, demographic, and political factors. These findings underscore the importance of targeted, context-specific public health strategies to reduce vaccination disparities and improve booster coverage in border regions.