Mexican-origin youth, as a large and growing population among U.S. youth, have been disproportionately affected by COVID-19. Understanding what, when, and how sociocultural factors may influence their COVID-19 vaccine uptake could inform current and future pandemic-response interventions promoting vaccination behaviors among Mexican-origin youth. The current study takes a developmental approach to reveal the long-term and short-term sociocultural antecedents of 198 Mexican-origin adolescents' COVID-19 vaccination uptake behaviors and explores the underlying mechanism of these associations based on the Knowledge-Attitude-Behavior model. The current study adopted Wave 1 (2012-2015) and Wave 4 (2021-2022) self-reported data from a larger study. Analyses were conducted to examine four mediation models for four sociocultural antecedents-daily discrimination, ethnic discrimination, foreigner stress, and family economic stress-separately. Consistent indirect effects of higher levels of concurrent sociocultural risk factors on a lower probability of COVID-19 vaccine uptake were observed to occur through less knowledge about the COVID-19 vaccines and less positive attitudes toward the COVID-19 vaccines at Wave 4. Significant direct effects, but in opposite directions, were found for the associations between Wave 1 ethnic discrimination/Wave 4 daily discrimination and the probability of COVID-19 vaccine uptake. The findings highlight the importance of considering prior and concurrent sociocultural antecedents and the Knowledge-Attitude-Behavior pathway leading to COVID-19 vaccination uptake among Mexican-origin youth and suggest that the impact of discrimination on COVID-19 vaccination uptake may depend on the type (e.g., daily or ethnic) and the context (e.g., during the COVID-19 pandemic or not) of discrimination experienced.