Introduction: Coronavirus Disease 2019 is a life-threatening disease, especially for people suffering from chronic diseases. As the vaccine is considered an essential tool to confront pandemics, many international medical institutions have developed vaccines. Countries around the world started immunizing their citizens. This study aims to assess the acceptance and barriers of COVID-19 vaccine uptake among Saudi Arabian people who suffer from chronic diseases. Methodology: In February-March 2021, a cross-sectional study of Saudi Arabian people who have chronic diseases was undertaken. It was based on an Arabic self-administered online questionnaire and used a convenience sampling technique. 310 people were invited. The response rate was 97%. Results: 51.95% of the participants agreed to take the COVID-19 vaccine, 33.5% were unsure about being vaccinated, and 14.5% refused. The most frequent concerns between participants and receiving the vaccine were about the side effects and the perceived misconception that following preventative measures is enough to protect against the virus. Significant associations between age, education, and occupation with acceptance rate were found (p < 0.05). Conclusions: Although a higher acceptance for the targeted group was expected, the participants showed a moderate acceptance of the COVID-19 vaccine. Addressing the barriers in the current study regarding vaccine uptake and focusing on building trust in the safety and efficacy of the vaccine will aid in hesitancy and resistance toward the vaccine, specifically if these measures were undertaken by an authority such as the Saudi Ministry of Health.