The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which began in late 2019, has resulted in approximately seven million deaths worldwide. This underscores the urgent need for vaccine and drug development. In silico techniques, especially molecular docking, provide promising means for discovering new treatments. This study aimed to identify novel compounds with potential activity against the nucleocapsid protein of SARS-CoV-2 using drug repositioning and bioisosterism techniques. We performed molecular docking with 20,115 compounds from the BindingDB database. The protein, obtained from the Protein Data Bank (PDB ID: 6WZQ), was prepared using MGLTools software, including protonation and removal of co-crystallized ligands and water molecules. We defined the binding site at the protein’s active site and used AutoDock Vina software for molecular docking, ranking the results based on relative binding energy. Interactions were visualized using Pymol and LigPlot+ software, focusing on hydrogen bonds and hydrophobic interactions. Compound BDBM6732 showed the most favorable binding energy (−13.4 kcal/mol), similar to the control compound suramin (−13.3 kcal/mol), but it was predicted to carry risks for hepatotoxicity and mutagenesis. We generated bioisosteres, resulting in two candidate analog compounds with superior affinity to four compounds referenced in the scientific literature, two of which had their activity validated in in vivo testing. These results suggest that the two analogs may potentially combat SARS-CoV-2 by binding to the nucleocapsid protein. However, validation in both in vitro and in vivo settings is essential.