We found that a number of cyclosporins were antiviral with similar potencies, including cyclosporine, cyclosporin A, cyclosporin B, and the metabolic breakdown product of cyclosporin A, isoscyclosporin A. To further address the role of calcineurin, we tested a non-immunosuppressant derivative of cyclosporine that does not inhibit calcineurin and has a similar activity to cyclosporin C. FK506, a calcineurin inhibitor independent of cyclophilin A, has no activity. Moreover, an NFAT inhibitor is not active. Altogether, these **data** suggest that cyclosporins are potent antivirals against SARS-CoV-2 in lung epithelial Calu-3 cells. Importantly, we found that the cyclophilin inhibitors that do not target calcineurin NIM811 and alisporivir have antiviral activity in both Calu-3 and Huh7.5 cells. However, the enzymatic activity of Cyclophilin A is likely dispensable because TMN355 was inactive. Strikingly, the activities of all of these drugs are similar in the two cell lines, suggesting that the activity is cell-type independent, inhibiting the same target using the same mechanism of action. To further support a dependence on cyclophilin in the human respiratory tract, we tested two additional models: iPSC-derived AT2 cells and primary human bronchial epithelial cells. We found that inhibition of cyclophilin was protective in both models. Altogether, our **data** suggest that alisporivir and cyclosporine would block SARS-CoV-2 in diverse infected tissues in vivo.