Orthopoxviruses remain a persistent global health concern due to the ongoing circulation of mpox, the possibility of the re-emergence of smallpox, and the threats posed by many poxviruses that infect animals and/or humans. The limited availability of antiviral drugs, the unproven efficacy in humans, and the emergence of resistant mutants underscore the need for new and better therapeutics. In this study, we identify and characterize ZW-2038, a hydroxypyridone-3-carboxamide analog, as an antiviral compound against vaccinia virus (VACV), monkeypox virus (MPXV), and cowpox virus (CPXV). Discovered through a focused in-house small-molecule screen, ZW-2038 exhibited low micromolar potency and high selectivity in primary human fibroblasts. The compound also reduced viral replication under physiomimetic conditions including human and monkey intestinal organoids (enteroids) and ex vivo mouse lung tissue models. Mechanistically, ZW-2038 suppresses VACV DNA replication and downstream post-replicative gene expression, albeit without inhibiting MPXV resolvase (Mpr) in vitro. These findings, along with in vitro safety profiling and mice pharmacokinetics studies, characterize ZW-2038 as a promising yet suboptimal antiviral lead against orthopoxviruses warranting future development.