Objectives: Effective implementation of prevention and control actions by health professionals is substantial to contain the deadly COVID-19 pandemic. Thus, this study aimed to assess health care worker’s practice of using personal protective equipment and psychological preparedness against the COVID-19 pandemic in Eastern Ethiopia. Methods: A facility-based cross-sectional study design was used. The health care workers (HCW) who were working in the selected health facilities were randomly selected. Variables that had p-value of < 0.15 were transformed to multivariable logistic regression model. Finally, the significance level was declared at the p-value < 0.05 with a 95% confidence interval (CI). Results: A total of 418 HCWs were randomly selected and included in this study. The study participants mean age was 27.96 years with a ±5.6SD. HCWs who were male (adjusted odds ratio(AOR) = 2.21, 95% CI: 1.29–3.79), regularly using sanitizer, accessing COVID-19 management guideline (AOR = 2.83, 95% CI: 1.46–5.47), trained on COVID-19 prevention methods (AOR = 2.6, 95% CI: 1.4–4.7), hopeless of eventually getting COVID-19 at workplace (AOR = 1.9, 95% CI: 1.13–3.28), and feeling unsafe at work when using standard precautions (AOR = 0.46, 95% CI: 0.27–0.79) were associated with good PPE using compared to their counterparts. Moreover, nursing/midwifery professionals practiced good personal protective equipment compared to physicians (AOR = 3.7, 95% CI: 1.8–7.7). Conclusion: The study demonstrated that being a male, being a nurse/midwifery, regularly sanitizing hands/medical equipment, having COVID-19 management guidelines, trained on COVID-19, and feeling of eventually getting COVID-19 at workplace had a positive association with PPE utilization. Besides, the study revealed that not feeling safe at work when using standard precautions was negatively associated with PPE utilization of HCWs. Therefore, the prevention priorities should be given to frontline HCWs by providing all possible support and strictly implementing the prevention and control guidelines of COVID-19 to prevent the health system from collapse.