Objectives: This study aimed to analyze the characteristics of coronavirus disease 2019 (COVID-19) infected health care workers (HCWs) and to measure their immunoglobulin G (IgG) response. Methods: This is a retrospective and prospective cohort study where details of COVID-19 infected HCWs were collected in a pre-designed database in Al-Nahdha Hospital between 2 April and 24 July 2020. A single serum sample was collected from participating HCWs to detect the presence of IgG in their sera. Results: Out of 974 HCWs, 103 (10.6%) were infected and tested positive for severe acute respiratory syndrome coronavirus 2 by real-time reverse transcriptase polymerase chain reaction. Nurses and doctors were the most affected groups. The source of infection was the hospital in 50.0% of cases. Nurses were more than four times likely to have a hospital-acquired COVID-19 infection (odds ratio = 4.63, 95% confidence interval: 1.71–12.52, p-value = 0.002). HCWs working in COVID-19 areas were more likely to have hospital-acquired infection than community-acquired infection (p < 0.005). All infected HCWs made a full recovery, with only 3.9% requiring admission. Out of 74 tested HCWs for IgG, 60 (81.1%) were positive. IgG positivity rate was significantly higher among HCWs in COVID-19 areas (p = 0.026) and among non-Omanis (p = 0.008). Moreover, the median IgG level was significantly higher among non-Omanis (p = 0.004). Conclusions: This study has highlighted the group at higher risk of hospital-acquired COVID-19 infection which was nurses and those working in COVID-19 areas. It highlighted as well the high seropositivity among this infected group. These findings support the national guidelines on priority groups for vaccination among HCWs working in COVID-19 areas with no previous laboratory-confirmed COVID-19.