Introduction: The World Health Organization (WHO) stated that coronavirus disease 2019 is considered as a pandemic on March 11, 2020.As the vaccination globally has proven its efficacy to prevent 2-3 million deaths per year and in order to control the spread of COVID-19 infection throughout the world, scientists exerted efforts and developed COVID-19 vaccine. This study aimed to assess the knowledge, attitude, and barriers toward COVID-19 vaccine among Saudi adults in Eastern Province. Methods:This is a cross-sectional study conducted through a self-administered questionnaire adapted from a published study in Jeddah titled effectiveness of influenza vaccination in elderly diabetic patients and was validated by the researchers. The questionnaires were distributed among adults who live in eastern part of Saudi Arabia during the period 2020 -2022. Data were entered and analyzed using SPSS program version 26. Results: sample size was calculated and found to be 462. The vast majority of the participants received 2 doses of COVID-19 vaccine (95.9%). Almost two-thirds (63.2%) have good level of knowledge about the COVID-19 vaccine. While the remaining one-third of the participants (36.8%) have poor knowledge about COVID-19 vaccine. Most of the participants will recommend COVID-19 vaccine for their friends and family members. Moreover, significantly higher percentage of high-income respondents (95%) were willing to accept the vaccine in comparison to 87.8% of low-income respondents. Conclusion:Overall, there is low level of COVID-19 vaccine knowledge among participants. However, their attitude toward vaccination is positive. The majority of respondents has no barriers toward acceptance of COVID-19 vaccine.