AbstractSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiological cause of the coronavirus disease 2019, for which no effective therapeutics are available. The SARS-CoV-2 main protease (Mpro) is essential for viral replication and constitutes a promising therapeutic target. Many efforts aimed at deriving effective Mproinhibitors are currently underway, including an international open-science discovery project, codenamed COVID Moonshot. As part of COVID Moonshot, we used saturation transfer difference nuclear magnetic resonance (STD-NMR) spectroscopy to assess the binding of putative Mproligands to the viral protease, including molecules identified by crystallographic fragment screening and novel compounds designed as Mproinhibitors. In this manner, we aimed to complement enzymatic activity assays of Mproperformed by other groups with information on ligand affinity. We have made the MproSTD-NMR data publicly available. Here, we provide detailed information on the NMR protocols used and challenges faced, thereby placing these data into context. Our goal is to assist the interpretation of MproSTD-NMR data, thereby accelerating ongoing drug design efforts.