Calcium signalling is important for entry of ebola virus (EBOV) into the host. Here, Sakurai et al. report that EBOV infection can be blocked in vitro by various calcium-channel antagonists — in particular, the small molecule tetrandrine. In vitro knockout, short interfering RNA (siRNA) and overexpression experiments revealed that two-pore channels were the specific calcium channels required for EBOV infection, and that these were inhibited by tetrandrine. Tetrandrine potently blocked EBOV infection of human monocyte-derived macrophages — an initial target of virus infection — and, when given every 2 days for a week to EBOV-challenged mice, eliminated virus and significantly enhanced survival.