Summary Background The current global coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has shown limited responses to medical treatments. Aims To observe the effect of combination treatment of giammonium glycyrrhizinate and vitamin C (DV) on the prognoses of patients with COVID-19. Methods This retrospective observational study recruited 207 COVID-19 patients from Tongji Hospital, patients were assigned to DV and non-DV groups on the basis of the DV treatment. To make the results more credible, a propensity score matching (PSM) approach was adopted at a 1:3 ratio to determine the participants. Logistic analysis was used to assess the effect of DV therapy in the progress of COVID-19. Results In the DV group, the new-onset incidence rate of acute respiratory distress syndrome (ARDS) after admission was clearly lower than that in the non-DV group (DV vs. non-DV groups, 15.2% vs. 35.7%; P = 0.002). Compared with the non-DV group, the DV group showed fewer new onset of complications (such as ARDS, acute liver injury and acute myocardial injury) (DV vs. non-DV groups, 19.6% vs. 46.1%; P = 0.000). Moreover, DG+VC may help to recover the count of NK cells and decrease the level of sIL-2R. Conclusions DG+VC might be a promising candidate for preventing the deterioration of COVID-19 patients, which is worthy to be studied in large and perspective cohort.