Background: COVID-19 vaccine mandates are considered a controversial public health policy both in public debate and among healthcare workers (HCWs). Thus, the objective of this systematic review is to give a deep insight into HCWs’ views and attitudes towards COVID-19 vaccination mandates amid the ongoing COVID-19 pandemic. Methods: A systematic literature search of five databases (PubMed, Scopus, Embase, CINAHL, and Web of Science) was conducted between July 2022 and November 2022. Original quantitative studies that addressed the attitudes of HCWs regarding COVID-19 vaccine mandates were considered eligible for this systematic review. All the included studies (n = 57) were critically appraised and assessed for risk of systematic bias. Meta-analyses were performed, providing a pooled estimate of HCWs’ acceptance towards COVID-19 vaccine mandates for: 1. HCWs and 2. the general population. Results: In total, 64% (95% CI: 55%, 72%) of HCWs favored COVID-19 vaccine mandates for HCWs, while 50% (95% CI: 38%, 61%) supported mandating COVID-19 vaccines for the general population. Conclusions: Our findings indicate that mandatory vaccination against COVID-19 is a highly controversial issue among HCWs. The present study provides stakeholders and policy makers with useful evidence related to the compulsory or non-compulsory nature of COVID-19 vaccinations for HCWs and the general population. Other: The protocol used in this review is registered on PROSPERO with the ID number: CRD42022350275.