Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiological cause of the coronavirus disease 2019, for which no effective antiviral 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 Mpro inhibitors 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 Mpro ligands to the viral protease, including molecules identified by crystallographic fragment screening and novel compounds designed as Mpro inhibitors . In this manner, we aimed to complement enzymatic activity assays of Mpro performed by other groups with information on ligand affinity . We have made the Mpro STD-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 Mpro STD-NMR data, thereby accelerating ongoing drug design efforts.