In order to use MOFs in virus decontamination processes, four archetypal MOFs with different metal clusters have been chosen: UiO-66 (Zr), HKUST-1 (Cu), MIL-53 (Fe) and MIL-125 (Ti). Five different concentrations (from 0.01 to 1 mg/mL) for each MOF and three different cell lines (Huh7 TMPRSS2, VeroE6 and Vero81.6) were investigated in aqueous medium (DMEM). Moreover, different cytotoxicity assays were evaluated (MTS, Neutral Red and LDH) and critically compared for the first time, with Neutral Red seemingly to be the most appropriate. HKUST-1 was found to be toxic above 0.1 mg/mL for all of the three cell lines, while the other three MOFs appear to be nontoxic, even above 1 mg/mL. Then, their effect against viruses was monitored, mainly for HCoV-229E and SARS-CoV-2, two different coronaviruses that still cause a lot of infection cases and deaths up to now. Following 1 hour contact with the viruses, HKUST-1 (Cu) and MIL-125 (Ti) were able to greatly diminish the viral titer by 86% and 79.2%, respectively, for HCoV-229E, whereas for SARS-CoV-2 HKUST-1 (Cu), MIL-53 (Fe) and UiO-66 (Zr), demonstrated an efficacy of 68.4%, 63.1% and 56.1%, respectively.