At present, SARS-CoV-2 is raging, and novel coronavirus pneumonia (COVID-19) has caused more than 35 million confirmed patients and more than 500 000 cases death, which seriously endanger human health, socioeconomic development, as well as global medical and public health systems. COVID-19 is highly contagious, has a long incubation period, and causes many death cases due to lack of effective specific treatment. Mesenchymal stem cells have powerful anti-inflammatory and immunoregulatory functions, and can effectively reduce the cytokine storm caused by coronavirus in patients, and improve the pulmonary fibrosis of patients, promote the repair of damaged lung tissue, and reduce the mortality. Currently, a number of related clinical trials of mesenchymal stem cell treatment of COVID-19 have been conducted, and have confirmed the safety and efficacy, suggesting a good clinical application prospect. While progress has been made in mesenchymal stem cell therapy for COVID-19, we should also catch sight of the problems and challenges faced by mesenchymal stem cell clinical trials under severe epidemic situation, including clinical trials design, stem cell quality management, and ethics in treatment. Only by paying attention to these can we guarantee the safe and effective development of mesenchymal stem cell clinical trials in the treatment of COVID-19.