Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the outbreak of coronavirus disease 2019 (COVID-19), which has been rapidly spreading. Several guideline therapies have been proposed as a possible treatment for SARS-CoV-2, however, these therapies are not sufficient to treat a severe condition of SARS-CoV-2 infection characterised by the increase of D-dimer and C-reactive protein (CRP) levels, and patchy ground-glass opacities (GGOs). Secretome-mesenchymal stem cells (S-MSCs) produced by MSCs under hypoxia could excessively release several anti-inflammatory cytokines and growth factors to control the COVID-19 cytokine storm and accelerate lung injury improvement. This is the first study investigating the clinical outcomes of three severe COVID-19 patients admitted to the intensive care unit of three different hospitals in Indonesia treated with S-MSCs. The decrease of D-dimer and CRP level was reported for all patients treated with S-MSCs. This was in line with improvement of pulmonary radiology, blood gas level, and hematologic assessment. In conclusion, these cases suggest that S-MSCs could effectively control D-dimer, CRP level and GGOs of severe COVID-19 patients associated with recovered pulmonary function.