While treatment with anti-SARS-CoV-2 agents holds promise for managing healthcare workers with COVID-19, studies on this topic are limited. This study evaluated the time to return-to-work and remaining symptoms among healthcare workers with COVID-19 who received ensitrelvir and those who did not receive anti-SARS-CoV-2 drugs. This observational cohort study included healthcare workers diagnosed with COVID-19 between June and September 2023 at a single facility in Japan. Participants returned to work if they met all the following criteria: ≥5 days post-COVID-19 onset, fever resolution, and negative antigen test. The primary endpoint was the days from disease onset to return-to-work. We also evaluated the persistence of each symptom on the date of return-to-work, and the clinical and virological outcomes on the first scheduled date of return-to-work (Trial registration: UMIN000054128). The study enrolled 60 participants in the ensitrelvir group and 42 in the non-antiviral group. The mean number of days (SD) to return-to-work was 6.9 days (±1.6) in the ensitrelvir group and 7.7 days (±1.9) in the non-antiviral group. On the date of return-to-work, 4 participants in the non-antiviral group had taste disorders and 2 had smell disorders. On the first scheduled date of return-to-work (i.e. the date of first antigen test after onset), 56.7 % of participants in the ensitrelvir group and 33.3 % in the non-antiviral group had recovered, with the antigen test negativity in 76.7 % and 52.4 %, respectively. Ensitrelvir treatment for healthcare workers experiencing COVID-19 appeared to be associated with early symptom amelioration with viral load reduction, and shorter time to return-to-work.