Background:The fight against the coronavirus disease (COVID-19), which has continued to threaten human existence globally, has led to the development of vaccines in order to control the rate of infection and death associated with the disease. Media messages on the COVID-19 vaccine are geared towards raising audience awareness and understanding of health risks, knowledge and attitudes about the vaccine safety. Objective: The study examined the knowledge and attitude towards COVID-19 vaccine safety media messages amongst residents of South East, Nigeria. Methods: A cross-sectional descriptive study was conducted among 399 respondents (18-47 years) in both urban and rural communities of South East, Nigeria from May 6th to July 4th, 2021. The survey was carried out using structured self administered questionnaire containing the respondents' demographics, knowledge and attitudes towards media messages regarding COVID-19 vaccine safety. The data were analysed using the SPSS version 26 software. Result was presented in frequencies, percentages and charts showing the interrelatedness of the variables examined. Regression ANOVA was used to test hypotheses on the extent to which level of exposure to COVID-19 media messages predict their knowledge and attitude towards COVID-19 vaccine safety at P<0.05 level of significance. Results: Data indicate respondents are apprehensive of taking the COVID-19 vaccine. Approximately, 91% of respondents are between the ages of 18 and 27 years. Meanwhile, 26.1% of the respondents agreed that media messages on COVID-19 vaccine is very assuring and convincing as regards human safety; 42.4% disagreed on the safety of COVID-19 vaccine safety messages; 26.1% rated vaccine messages as moderate as regards human safety, while 5.5% rated the vaccine messages as poor. Knowledge of respondents regarding the safety of the vaccine was low and respondents' attitude was negative in South East, Nigeria. The implication is indicative of the failure of the main stream media in educating the general public on pertinent health issues relevant to them. Conclusion: Knowledge regarding media messages on COVID-19 vaccine safety is low. Messages on COVID-19 vaccine safety were not sufficient and convincing. Consequently, there is a negative attitude towards the vaccine. Hence, improving knowledge and adoptive attitude amongst respondents amidst COVID-19 is critical.