In 2020, the Food and Drug Administration granted emergency use authorization for two COVID-19 vaccines. Two years later, the Centers for Disease Control and Prevention estimated that more than 250 million individuals had received at least one dose of the vaccine. Despite the large numbers of individuals vaccinated against COVID-19, partisan differences surrounding the COVID-19 vaccine emerged, creating a potential challenge for health communications aimed at increasing vaccine uptake. A better understanding of partisan differences in attitudes and intentions towards vaccination may help guide public health strategies aimed at increasing vaccine uptake. To determine whether a commonly used theory of behavioral intentions used to craft public health messages explains partisan differences in intentions. Data were drawn from a national panel of US adults and collected between February 21, 2022, and March 3, 2022, using an online survey (n = 1845). Among respondents identifying as either Democrat or Republican (n = 1466), path analysis models were estimated to test whether partisan differences in vaccination or booster intentions were explained by the theoretical constructs of protection motivation theory (PMT). PMT accounted for approximately half of the covariate-adjusted mean difference in COVID-19 vaccination intentions between Democrats and Republicans, and nearly all the mean difference in booster intentions. Party affiliation indirectly affected intentions via its association with perceived susceptibility to COVID-19, vaccine/booster efficacy, and perceived costs of getting a COVID-19 vaccine or booster dose. Compared with Democrats, Republicans may be less likely to get vaccinated or receive a booster dose because of beliefs that they are less susceptible to COVID-19, that the vaccine is less effective, and that vaccination comes with disadvantages. Theories of behavioral intentions can help to identify the underlying theoretical determinants driving behavioral differences between political groups.