The spread of coronavirus disease 2019 (COVID‐19) viral pneumonia caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) has become a worldwide pandemic claiming several thousands of lives worldwide. During this pandemic, several studies reported the use of COVID‐19 convalescent plasma (CCP) from recovered patients to treat severely or critically ill patients. Although this historical and empirical treatment holds immense potential as a first line of response against eventual future unforeseen viral epidemics, there are several concerns regarding the efficacy and safety of this approach. This critical review aims to pinpoint the possible role of mass spectrometry‐based analysis in the identification of unique molecular component proteins, peptides, and metabolites of CCP that explains the therapeutic mechanism of action against COVID‐19. Additionally, the text critically reviews the potential application of mass spectrometry approaches in the search for novel plasma biomarkers that may enable a rapid and accurate assessment of the safety and efficacy of CCP. Considering the relative low‐cost value involved in the CCP therapy, this proposed line of research represents a tangible scientific challenge that will be translated into clinical practice and help save several thousand lives around the world, specifically in low‐ and middle‐income countries.