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Aims/Background The coronavirus disease 2019 (COVID-19) pandemic has significantly impacted global health and the economy. Vaccination is crucial for controlling its spread, and healthcare workers (HCWs) in Saudi Arabia prioritize vaccination. This systematic review aimed to: (1) evaluate the reported side effects of COVID-19 vaccines among HCWs in Saudi, (2) assess vaccine acceptance rates and their temporal changes, and (3) identify the factors influencing vaccine uptake and hesitancy. Methods We conducted a systematic review following preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. The protocol included: (1) systematic searching of five major databases (MEDLINE, Embase, PubMed, Scopus, and Web of Science) up to 25 November 2024; (2) independent screening and selection by three reviewers using predefined inclusion criteria; (3) quality assessment using the Joanna Briggs Institute (JBI) critical appraisal tool; and (4) standardized data extraction and synthesis focusing on vaccine side effects, acceptance rates, and influencing factors among healthcare workers in Saudi Arabia. Results Of the 220 citations, 30 met the inclusion criteria. Studies have revealed predominantly mild to moderate side effects, with severity patterns varying by professional role and demographic factors. Vaccine acceptance showed significant improvement over time, which was attributed to public health campaigns, peer influence, and improved accessibility. Higher acceptance was correlated with professional experience and education levels, while hesitancy stemmed from safety concerns and efficacy doubts. Conclusion Understanding these patterns supports the development of targeted interventions, suggesting a need for evidence-based communication and peer-led education programs. Healthcare institutions should focus on transparent safety communication and address specific misconceptions to enhance vaccine confidence among HCWs.