In the 21st century alone, the world has faced the devastating impacts of three acute respiratory diseases: Middle East Respiratory Syndrome (MERS), Severe Acute Respiratory Syndrome (SARS), and COVID-19, which evolved into a pandemic. These diseases have not only caused a large number of deaths but have also damaged the economies of the affected regions. In particular, countries in the Latin American and Caribbean (LAC) region have faced additional challenges due to greater social inequalities, limited access to health services, and precarious living conditions. Therefore, it is imperative to understand the effects of mitigation actions to guide actions to mitigate the health and socioeconomic impacts if (or when) new acute respiratory diseases emerge, especially in these countries. A retrospective study was conducted to model the dynamics of variation in COVID-19 mortality in LAC countries and analyze its association with vaccination strategies, containment measures, mobility restrictions, and socioeconomic factors. The study methodology applied clustering techniques that revealed two distinct clusters based on sociodemographic characteristics, followed by the application of XGBoost to model the dynamics of variation in deaths in the countries of each cluster, over time. Finally, the SHAP Values technique was applied to understand the associations between mortality and factors such as vaccination, containment measures and mobility restrictions. In addition, a panel of experts was held to assess the relevance and effectiveness of the results found. The study provides evidence that economic support and the completion of the vaccination scheme were especially relevant in reducing COVID-19 mortality. It was possible to detect two distinct groups of countries, where one group may have characteristics of greater vulnerability than the other group. The most important interventions for understanding COVID-19 mortality varied in two distinct periods of the pandemic: pre-vaccination and post-vaccination. In the pre-vaccination period, containment measures were the most important interventions for mortality in the least vulnerable countries, while for the most vulnerable countries, they were variations in population mobility. In the post-vaccination period, vaccination coverage was the most important intervention for mortality in the least vulnerable countries, while the most vulnerable countries were more impacted by containment measures.