SARS-CoV-2 main protease–a vital enzyme for virus replication is a potential target for developing drugs in COVID-19 treatment. Until now, three SARS-CoV-2 main protease inhibitors have been approved for COVID-19 treatment. This study explored the inhibitory potency of asymmetric imidazole 4,5-dicarboxamide derivatives against SARS-CoV-2 main protease. Fourteen derivatives were designed on the structure of the SARS-CoV-2 main protease active site, the hydrolysis mechanism, and the experience gained from the reported inhibitor structure. They were synthesized through a four-step procedure from imidazole and methylimidazole. SARS-CoV-2 main protease inhibition was evaluated in vitro by fluorogenic assay with lopinavir, ritonavir, and ebselen as positive references. N-(4-chlorophenyl)-2-methyl-4-(morpholine-4-carbonyl)-1H-imidazole-5-carboxamide (5a2) exhibited the highest potency against SARS-CoV-2 main protease with IC50 of 4.79 ± 1.37 µM relative to ebselen IC50 of 0.04 ± 0.013 µM. Enzyme kinetic and molecular docking studies were carried out to clarify the inhibitory mechanism and to prove that the compound interacts at the active site. We also performed the cytotoxicity assay to confirm that these compounds are not toxic to the human cells.