Introduction: The expedited COVID-19 vaccine has challenged people’s belief and perception of its effectiveness. The purpose of this study was to identify whether knowledge related to Covid-19 and perception of effectiveness of Covid-19 vaccine would predict health-care workers’ willingness to take the vaccine. Methods: A cross-sectional design using a convenience sampling technique was used to collect data from 302 HCWs. HCWs targeted included all those working at healthcare settings in Jordan. Data collected regarding knowledge related Covid-19 and perception of effectiveness of Covid-19 vaccine. Data collected using a self-administered questionnaire. Results: HCWs have moderate to high level of knowledge related to vaccines of Covid-19 and its effectiveness. High level of willingness to take the vaccine was also observed among HCWs. Those with higher level of knowledge and positive perception of effectiveness of Covid-19 vaccine are more likely to take the vaccine (p < .05); however, not highly influential (R2 = 27%). Demographic characteristics have not been found to influence HCWs’ decision to take the vaccine. Conclusion: There is a need to enhance positive perception of effectiveness of Covid-19 vaccine among health professionals through appropriate education and procedures.