Background: SARS-CoV-2 is the coronavirus responsible for the COVID-19 pandemic. Although it poses a substantial public health threat, antiviral regimens against SARS-CoV-2 remain scarce. Here, we evaluated the antiviral potential of UV-4B, a host targeting antiviral, against SARS-CoV-2 in clinically relevant human cell lines. Methods: Cells derived from human lung (A549 cells transfected with human angiotensin converting enzyme 2 receptor (ACE2; ACE2-A549)) and colon (Caco-2) were infected with either a wild type or beta variant strain of SARS-CoV-2 and exposed to various concentrations of UV-4B. Supernatant was sampled daily and viral burden was quantified by plaque assay on Vero E6 cells. Results: Therapeutically feasible concentrations of UV-4B inhibited the replication of the wild type strain in ACE2-A549 and Caco-2 cells yielding EC{}_{50} values of 2.694 and 2.489 \muM, respectively. UV-4B’s antiviral effect was also robust against the beta variant in both cell lines (ACE2-A549 EC{}_{50}: 4.369 \muM; Caco-2 EC{}_{50}: 6.816 \muM). Conclusions: These results highlight UV-4B’s antiviral potential against several strains of SARS-CoV-2.