Background: Healthcare workers (HCWs) are faced with an elevated risk of exposure to SARS-COV-2 due to the clinical procedures they perform on COVID-19 patients. However, data for frontline HCWs level of exposure and risk of COVID-19 virus infection are limited. Objective: We investigated the level of exposure and risk of COVID-19 virus infection among HCWs in COVID-19 treatment centers in Ghana. Methods: A cross-sectional study was utilized in this study and HCWs were invited by convenience to participate in the study, 408 HCWs in 4 COVID-19 treatment centers participated in the study. Adherence to infection prevention and control (IPC) measures were used to categorized HCWs as low or high risk of COVID-19 virus infection. The WHO COVID-19 risk assessment tool was used to collect quantitative data from the study participants. Results: There was a high (N = 328, 80.4%) level of occupational exposure to the COVID-19 virus. However, only 14.0% of the exposed HCWs were at high risk of COVID-19 virus infection. Healthcare workers who performed or were present during any aerosol-generating procedures (AGP) were 23.8 times more likely to be exposed compared to HCWs who did not perform or were absent during any AGP (AOR 23.83; 95% CI: 18.45, 39.20). High risk of COVID-19 virus infection was less likely among registered nurses (AOR = 0.09; 95% CI: 0.02, 0.60), HCWs who performed or were present during any AGP (AOR = 0.05; 95% CI: 0.01, 0.50) and HCWs with a master’s degree qualification (AOR 0.06; 95% CI: 0.01, 0.63). Conclusion: Despite the high level of exposure to the COVID-19 virus among HCWs in the treatment centers, only 14.0% were at high risk of COVID-19 virus infection. To protect this group of HCWs, treatment centers and HCWs should continue to adhere to WHO and national IPC protocols in managing of COVID-19 cases.