Poxviruses remain a significant global health concern, necessitating the development of novel antiviral strategies. Through high-throughput screening, we previously identified ciclopirox (CPX), an FDA-approved antifungal, as a hit that inhibits vaccinia virus (VACV) replication. Here, we further characterized its antiviral activity and mechanism of action using human primary fibroblasts. CPX significantly reduced VACV titers without reducing host cell viability, with an EC in the sub-micromolar range and a CC >500 μM. Rescue experiments demonstrated that CPX inhibits viral replication primarily through chelation of intracellular Fe and, to a lesser extent, Fe, as evidenced by partial restoration of viral replication with ferric ammonium citrate supplementation. Furthermore, overexpression of the iron-dependent enzymes RRM2 and the VACV-encoded F4L reduced the inhibitory effect of CPX, indicating that these host and viral proteins are affected by CPX treatment. Moreover, CPX treatment also suppressed cowpox virus and monkeypox (mpox) virus replication . It also reduced VACV titers in mouse lung tissue. These findings highlight host iron metabolism as a critical determinant of poxvirus replication and support repurposing CPX as a broad-spectrum orthopoxvirus antiviral candidate.