SARS-CoV-2, the COVID-19 pathogen, relies on its main protease (M) for replication and pathogenesis. M is a demonstrated target for the development of antivirals for SARS-CoV-2. Past studies have systematically explored tripeptidyl inhibitors such as nirmatrelvir as M inhibitors. However, dipeptidyl inhibitors especially those with a spiro residue at their P2 position have not been systematically investigated. In this work, we synthesized about 30 dipeptidyl M inhibitors and characterized them on enzymatic inhibition potency, structures of their complexes with M, cellular M inhibition potency, antiviral potency, cytotoxicity, and metabolic stability. Our results indicated that M has a flexible S2 pocket to accommodate inhibitors with a large P2 residue and revealed that dipeptidyl inhibitors with a large P2 spiro residue such as ()-2-azaspiro [4,4]nonane-3-carboxylate and ()-2-azaspiro[4,5]decane-3-carboxylate have favorable characteristics. One compound, MPI60, containing a P2 ()-2-azaspiro[4,4]nonane-3-carboxylate displayed high antiviral potency, low cellular cytotoxicity, and high metabolic stability.