With the mass vaccination program for COVID-19 mRNA vaccines, there has been sufficient real-world study (RWS) on the topic to summarize their safety in the total population and in immunocompromised (IC) patients who were excluded from phase 3 clinical trials. We conducted a systematic review and meta-analysis to evaluate the safety of COVID-19 mRNA vaccines, with a total of 5,132,799 subjects from 122 articles. In the case of the total population vaccinated with first, second, and third doses, the pooled incidence of any adverse events (AEs) was 62.20%, 70.39%, and 58.60%; that of any local AEs was 52.03%, 47.99%, and 65.00%; that of any systemic AEs was 29.07%, 47.86%, and 32.71%. Among the immunocompromised patients, the pooled odds ratio of any AEs, any local AEs, and systemic AEs were slightly lower than or similar to those of the healthy controls at 0.60 (95% CI: 0.33–1.11), 0.19 (95% CI: 0.10–0.37), and 0.36 (95% CI: 0.25–0.54), with pooled incidences of 51.95%, 38.82%, and 31.00%, respectively. The spectrum of AEs associated with the vaccines was broad, but most AEs were transient, self-limiting, and mild to moderate. Moreover, younger adults, women, and people with prior SARS-CoV-2 infection were more likely to experience AEs.