Background Sentiments and opinions regarding COVID-19 and the COVID-19 vaccination on Indonesian-language Twitter are scarcely reported in one comprehensive study, and thus were aimed at our study. We also analyzed fake news and facts, and Twitter engagement to understand people’s perceptions and beliefs that determine public health literacy. Methods We collected 3,489,367 tweets data from January 2020 to August 2021. We analyzed factual and fake news using the string comparison method. The difflib library was used to measure similarity. The user’s engagement was analyzed by averaging the engagement metrics of tweets, retweets, favorites, replies, and posts shared with sentiments and opinions regarding COVID-19 and COVID-19 vaccination. Result Positive sentiments on COVID-19 and COVID-19 vaccination dominated, however, the negative sentiments increased during the beginning of the implementation of restrictions on community activities (PPKM). The tweets were dominated by the importance of health protocols (washing hands, keeping distance, and wearing masks). Several types of vaccines were on top of the word count in the vaccine subtopic. Acceptance of the vaccination increased during the studied period, and the fake news was overweighed by the facts. The tweets were dynamic and showed that the engaged topics were changed from the nature of COVID-19 to the vaccination and virus mutation which peaked in the early and middle terms of 2021. The public sentiment and engagement were shifted from hesitancy to anxiety towards the safety and effectiveness of the vaccines, whilst changed again into wariness on an uprising of the delta variant. Conclusion Understanding public sentiment and opinion can help policymakers to plan the best strategy to cope with the pandemic. Positive sentiments and fact-based opinions on COVID-19, and COVID-19 vaccination had been shown predominantly. However, sufficient health literacy levels could yet be predicted and sought for further study.