This paper examined the knowledge of COVID-19 safety measures among health workers in Edo State, Nigeria, and determined whether knowledge differed according to sex, age, years of work experience, and educational qualification. A descriptive cross-sectional research design was adopted. The population comprised 3,223 health workers from Irrua Specialist Teaching Hospital, Irrua, University of Benin Teaching Hospital, and Central Hospital, Benin City. A sample of 1,617 health workers was selected using a stratified random sampling technique, while 1,601 completed questionnaires were available for analysis. Data were collected using a researcher-developed questionnaire structured into sections covering demographic characteristics and knowledge of COVID-19 safety measures. The instrument demonstrated acceptable reliability, with a split-half reliability coefficient of 0.78 for knowledge. Data were analysed using mean, standard deviation, and independent-samples t-test at the 0.05 level of significance. Findings revealed that health workers had good overall knowledge of COVID-19 safety measures, with an overall mean score of 2.07 on a three-point scale. Respondents demonstrated good knowledge of regular handwashing (2.23), use of alcohol-based hand sanitizers (2.20), avoidance of handshaking (2.11), and taking COVID-19 vaccine doses (2.09). However, knowledge was poor regarding covering the mouth while coughing with the elbow (1.95), maintaining social distancing (1.93), and avoiding frequently touched surfaces (1.96). Significant differences in knowledge were found by sex (t = - 7.088, p < 0.05), age (t = -2.071, p = 0.039), work experience (t = -5.736, p < 0.05), and educational qualification (t = -6.255, p < 0.05). Female, older, more experienced, and better-educated health workers had higher knowledge scores than their respective counterparts. The study concluded that health workers in Edo State possessed good knowledge of COVID-19 safety measures, although specific gaps remained in some preventive practices. It was recommended that targeted and continuous training programmes be provided, particularly for younger, less experienced, and lessqualified staff, to strengthen knowledge and adherence to COVID-19 safety measures.