The infections and deaths resulting from Coronavirus Disease 2019 (COVID-19) triggered the need for some governments to make COVID-19 vaccines mandatory. The present study aims to analyze the position of 3026 adults in Colombia, El Salvador, and Spain regarding the possibility of making COVID-19 vaccine mandatory and the intention to be vaccinated with the booster or possible successive doses. Data from an online survey conducted from August to December 2021 among a non-representative sample of Spanish-speaking countries were collected. Multinomial Logistic Regression Models were used. A total of 77.4% of Colombians were in favor of mandatory vaccination compared to 71.5% of Salvadorians and 65.4% of Spaniards (p < 0.000). Women and people over 65 years of age were the groups most in favor of making the vaccine mandatory (p < 0.000). A total of 79.4% said they had received a third dose or would intend to receive the third dose or future doses, if necessary, compared with 9.4% who expressed doubts and 9.9% who refused to be vaccinated or did not intend to be vaccinated. Among the measures that could be taken to motivate vaccination, 63.0% and 60.6% were in favor of requiring a negative test to enter any place of leisure or work, respectively, compared to 16.2% in favor of suspension from work without pay. The acceptance of mandatory vaccination and of third or future doses varies greatly according to sociodemographic characteristics and work environment. As such, it is recommended that policy makers adapt public health strategies accordingly.