Introduction The best way to eradicate corona virus disease (COVID-19) viral infection is mass vaccination. Many studies demonstrate vaccination is associated with some local and systemic side effects. This study aimed to provide evidence on AstraZeneca COVID-19 vaccine side effects. Methodology Institutional based cross-sectional survey was conducted among 254 health workers at Nigist Eleni Mohammed memorial comprehensive specialized hospital (from July 01/ 2021 to July 30/2021). Data were collected consecutively through self-administered online survey created on Google Forms of platform which had been randomly delivered via (Facebook or telegram pages). Demographic data of participants, side effect after first and second dose of vaccine were covered. Result The prevalence of at least one side effect after first dose was 91.3% and after second dose was 67%. Injection site pain (63.8% vs. 50.4%), headache (48.8% vs. 33.5%), fever (38.8% vs. 20.9%), muscle pain (38.8% vs. 21.7%), fatigue (26% vs. 28.7%, tenderness at the site (27.6% vs. 21.7%), and joint pain (27.6% vs. 20.9%) were the most commonly reported side effects after first and second dose vaccine respectively. Most of participants reported that their symptoms emerged after 6hr of vaccination and only less than 5% of participant’s symptoms lasted more than 72hr of post vaccination. The younger age (≤29 year) were more susceptible to at least one side effect (χ 2 = 4.2; p = 0.04) after first dose. Conclusion The prevalence of side effect after first and second dose vaccine was higher. Most of the symptoms were short lived and mild. This result might help to solve an emerging public health challenge (vaccine hesitancy) nurtured by misinformation related to vaccines safety.