The global coronavirus disease 2019 (COVID-19) pandemic, caused by the highly infectious severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), had resulted in significant mortality worldwide. In 2020, the World Health Organization started the solidarity clinical trial to assess the efficacy of four proposed therapeutic strategies, including chloroquine (CQ), a 4-aminoquinoline molecule. However, CQ lacks clinical benefit and, therefore, failed to show in vitro anti-SARS-CoV-2 activity in TMPRSS2-expressing cells, such as Calu-3 cell line, which recapitulate human type II pneumocytes. Nevertheless, other 4-aminoquinoline derivatives have shown high affinity toward the SARS-CoV-2 main protease (Mpro). This study aimed to evaluate, in vitro and in silico, the inhibitory potential of nine 4-aminoquinoline derivatives against SARS-CoV-2, building upon the observed antiviral activity of established antimalarial drugs. We assessed the ability of these derivatives to inhibit SARS-CoV-2 (wild type and Omicron variant) replication in Vero E6 and Calu-3 cell lines. In addition, we conducted docking studies to determine the binding affinity and protein-ligand interactions. Notably, these derivatives exhibited potent antiviral activity with low cytotoxicity in Vero E6 and Calu-3 cell models. In silico investigations targeting the Mpro enzyme supported the potential of the derivatives as promising agents in the fight against SARS-CoV-2. Our findings underscore the potential of these 4-aminoquinoline derivatives as robust inhibitors of SARS-CoV-2 and advocate for further research to explore their therapeutic applications, providing valuable insights for future drug development strategies.