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Vaccination is the most promising approach for ending or containing the SARS-CoV-2 pandemic. However, serious post-COVID-19 vaccine reactions, including immunocytopenia (ITP) syndrome, have been increasingly reported. Several factors cause increased risks including multiple doses, age-dependent heterogeneity in immune-responses, platelet cross-reactions with microbial components, and Long-COVID syndrome. Thus, in the absence of widely available specific therapeutics, vigilance is important while more studies are needed. Using a structured questionnaire sent to different regions in Saudi Arabia, we conducted a comprehensive investigation on the frequency, rates, disease patterns, and patient demographics of post-COVID-19 vaccine side effects on febrile patients after administration three major vaccines. Results indicated that the majority of respondents administered Pfizer BioNtech vaccine (81%, n = 809); followed by AstraZeneca (16%, n = 155); and Moderna (3%, n = 34). Overall 998 participants, 74% (n = 737) showed no serious symptoms; however, 26.2% (n = 261) revealed typical syndromes. In a focused group of 722 participants, the following rates were identified: shortness of breath (20%), bruises or bleeding (18%), inattention (18%), GIT symptoms (17.6%), skin irritation (8.6%), and anosmia and ageusia (8%) were the most prominent among those who showed typical symptoms. The onset time was mostly between 1–3 days in 49% (n = 128), followed by 4–7 days in 21.8% (n = 57), 8–14 days in 16.5% (n = 43), and more than a month in 12.6% (n = 33). The onsets occurred mostly after the first, second, or both doses, 9%, 10%, and 7% of participants, respectively. The frequency of symptoms was significantly higher after Moderna® vaccine (p-value = 0.00006) and it was significantly lower in participants who received Pfizer (p-value = 0.00231). We did not find significant difference in symptoms related to differences in regions. Similarly, the region, age, sex, education, and nationality had no influence on the dose and onset timings. The findings of this study have significant clinical implications in disease management strategies, preventive measures, and vaccine development. Future vertical studies would reveal more insights into the mechanisms of post-COVID-19 vaccine syndrome.