The coronavirus disease 2019 (COVID-19) pandemic is a complex, highly dynamic problem with negative impacts on health and socio-economics aspects, both nationally and internationally. In addition to the direct impacts on the health of COVID-19 patients, the pandemic also affected the provision of healthcare services for patients with many other diseases and conditions. Policymakers in Thailand and around the world are trying to take measures to deal with the outbreak to reduce its consequences with two major groups of disease control policies: by general measures (non-pharmaceutical interventions: NPI) and by using drugs or vaccines (on-pharmaceutical interventions: PI). At the beginning of the pandemic there were no drugs or vaccines to control COVID-19. Many countries around the world therefore focus on an enforcement of non-pharmaceutical interventions, such as a ban on travels in and out of the country, limited people going out of residence for certain periods (curfew), the closure of government buildings and the suspension of social and business activities, physical distancing and personal hygiene campaign. Yet, these non-pharmaceutical interventions measures are of limited effectiveness when applied over the long term, and also have serious economic and social impacts. Due to the severity of COVID-19 that affects the health of the infected persons and the limitation of NPIs, agencies around the world, both public and private, have accelerated research studies to develop anti-COVID-19 vaccines. While many vaccines have been developed and proven to be effective in humans, there are still challenges and difficulties in implementing them at the population level. This is because newly developed vaccines need to be certified and allowed before being used for a larger population. There are also limitations in terms of its long-term safety that have not been comprehensively assessed. Some of the vaccines being developed by new technologies that require specialized storage and transportation that may not be suitable for use in many contexts. Lastly, the number of vaccines produced at an early stage is still insufficient to meet both global and national demands. Therefore, without a well-informed policy decision to manage the COVID-19 vaccine supply chain, the policy makers not even achieve the effectiveness of disease control, may cause unnecessary loss of life, and even create health inequity. Not only the COVID-19 pandemic is a complex problem with high dynamics, policy decisions regarding the anti-COVID-19 vaccines are also very complex with uncertain results. We applied systems thinking process to deal with complexities and uncertainties by reviewing the related vaccine literature and conducting system dynamics modeling of the epidemic situations with vaccinating the anti-COVID-19 in Thailand’s populations. Group model building (GMB) process was used to work with policymakers and stakeholders of the COVID-19 vaccine policies. The Susceptible-Exposed-Infectious-Recovered (SEIR) model customarily used for epidemiological forecasting can be modified to build a structure of system dynamics (SD) models that simulated the scenarios emerging from various COVID-19 vaccine policy decisions. The target populations and the prioritization among the target groups were considered when considering which options can lead to the most effectiveness, and with the least unexpected results. We found that the data needed for developing simulation modeling of the anti-COVID-19 vaccines in Thailand had been very limited. But our literature review and consultations with experts led to sufficient data to construct a system dynamics model. We modeled the epidemiological scenarios during the April 2021 outbreak in Thailand, where the vaccines was somewhat effective in preventing infection but only limited supplies of vaccines available domestically, not enough for all population groups. The findings from our simulation model suggested that, deaths would be lower if the policymakers prioritized vaccines to people living in hyperendemic rather than distributing them across the country. Even though empirical evidence suggests that the vulnerable populations had a greater risk of developing severe symptoms and deaths if infected, allocating the vaccines to both the healthy and vulnerable populations can lead to less number of deaths than vaccinating only the vulnerable. As for the results from a situational model during the January 2022 outbreak with Omicron strain, as Thailand started to secure sufficient doses of vaccines yet the vaccines become less effective in preventing COVID-19 infections. This, the policy option of procuring and allocating a booster dose of COVID-19 vaccine to vulnerable populations becomes critical to reducing the COVID-19 case-fatality rate. Lastly, after the populations fully vaccinated or the immune levels of the previously infected reduced over time (vaccination waning), there is a chance of a new wave of outbreaks domestically. Therefore, policymakers should continue monitoring a set of indicators for effective policy decision-making on vaccination and other disease control policies in the first quarter of 2022, particularly when the vaccination coverage of the booster-dose vaccine was still less than desirable. With the Omicron strain, two doses of vaccination became not sufficient to prevent the symptomatic infections caused by infection. Other policy deployment mechanism to speed up the vaccination coverage, especially in the health-sensitive population groups, would reduce the severity of another wave of severe infections and deaths in 2022. The preliminary results of our research have been presented to policymakers at different levels to support their decision-making process. These included the scientific advisory committees of The Centre for COVID-19 Situation Administration (CCSA) of the Royal Thai Government, The Emergency Operation Center (EOC) of The Ministry of Public Health, The Macroeconomics Department of the Central Bank of Thailand, and The Board of Directors of the Health Systems Research Institute. Yet, using system dynamics modeling as a policy decision support tool (DST) still has limitations. The public policy process to cope with Thailand's public health emergencies tends to focus more on reactive measures than on planning and addressing the structural issues of the health systems that created persisting problems during the COIVD-19 pandemic. Without policies that address the high-leverage point of the systems, many issues related to the management of the COVID-19 vaccine supply chain still persists, including confusing communication of the risks of vaccination versus no vaccination to the public. Therefore, it is crucial to create a learning platform among policymakers and stakeholders to synthesize lessons learned on integrating research in the public policy process, and focusing more on the evidence-informed policy-making process under the country's emergency management systems. It can be challenging for policymakers to use evidence from simulation modeling in the decision-making process amid uncertain information and pressure from the public. But it is vital to work on this complex problem-solving process to prepare for any soon emerging public health emergencies.