Background The initial response to coronavirus disease 2019 (COVID-19) was non-pharmaceutical interventions (NPIs). Long-term protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection does not appear to be possible by either infection or vaccination. Thus, traditional herd immunity seems impossible. In addition to increasing vaccination rates, NPIs may be needed. Methods A facility-based cross-sectional study was conducted among vaccinated healthcare workers. The study took place from July 15 to August 15, 2022. A self-administered questionnaire was used for data collection. In a multivariable logistic regression model, a p-value of less than 0.05 was considered statistically significant. Results Four hundred eleven healthcare workers were included in the study. Sixty percent of participants were fully vaccinated. After vaccination, 10.2% of respondents reported infection with SARS-CoV-2. The study showed that 49.4% of participants had a good knowledge of the efficacy and safety of vaccines against SARS-CoV-2. In this study, 36% of individuals adhered well to the COVID-19 prevention strategies. Good knowledge of the efficacy and safety of SARS-CoV-2 vaccines (AOR = 1.69, 95% CI: 1.03–2.78) increased the odds of implementing preventive measures. Healthcare workers who perceived a low and medium risk of SARS-CoV-2 infection after vaccination and who were knowledgeable about SARS-CoV-2 breakthrough infections were less likely to follow preventive measures. Conclusion The knowledge of healthcare workers regarding the efficacy and safety of vaccines against SARS-CoV-2 was comparable. However, a large proportion of healthcare workers poorly adhered to prevention practices. Therefore, to reduce the risk of SARS-CoV-2 infection among healthcare professionals, prevention strategies must be continuously evaluated and awareness of the need for preventive measures must be raised even after vaccination.