Despite many years of investigation into mesenchymal stem cells (MSCs) and their potential for treating inflammatory conditions such as COVID-19, clinical outcomes remain variable due to factors like donor variability, different tissue sources, and diversity within MSC populations. Variations in MSCs' secretory and proliferation profiles, and their proteomic and transcriptional characteristics significantly influence their therapeutic potency, highlighting the need for standardized and enhanced characterization methods to better predict their efficacy. This study aimed to evaluate the biological characteristics and therapeutic efficacy of MSCs from different tissue origins, selecting the most promising line for further validation in a K18-hACE2 mouse model of SARS-CoV-2 infection.