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Abstract Background A safe and effective vaccine is the ultimate key to mitigating the COVID-19 pandemic. Vaccine acceptance is influenced by various factors, including perceptions about the vaccine’s safety and side effects. The side effects vary depending on the type of the vaccine, but they are mainly mild, local, temporary, and self-limiting. Methods A cross-sectional study was carried out at Tanta University Hospitals, including 1246 healthcare workers who received either the first or the second dose of the COVID-19 vaccine, selected via a systematic random sampling technique using a self-administered structured validated questionnaire for data collection from November 2021 to January 2022. Qualitative data were presented as frequencies and percentages and analyzed using Chi-square and Fisher’s exact tests. Results The prevalence of one or more side effects was 91.3%. Among participants, about two-thirds believed in vaccine safety and its necessity (65.4% and 63.6%, respectively). Significantly more participants (46.9%) were concerned about AstraZeneca thrombotic complications than other vaccine types. The top five side effects reported by participants were injection site pain (64.8%), sense of fatigue (57.1%), headache (49.9%), muscle pain (48.7%), and fever (46.5). Most of the side effects were significantly higher among participants vaccinated with AstraZeneca. Side effects impacted work capacity of 23.4%, which was significantly higher among participants who received AstraZeneca (33.6%). Conclusion Participants had a good level of belief in vaccination safety and necessity. Healthcare workers who got the AstraZeneca vaccination reported more adverse effects than other vaccines. Injection site pain, fatigue, headache, muscle pains, and fever were the most frequently reported side effects. More research on vaccination safety is needed to understand the long-term adverse effects of vaccinations better, improve the public trust, and accelerate vaccine adoption.