The study presents the discovery of a novel class of N-arylated 1,2,4-oxadiazol-5(4H)-ones as potent inhibitors of orthopoxviruses, including the variola virus (VARV). Through systematic structural modifications, two lead compounds, 4 (4-CF3/4-NO2) and 10 (4-I/4-NO2), demonstrated in submicromolar concentration antiviral activity against Vaccinia virus (VACV), cowpox virus (CPXV), ectromelia virus (ECTV), and VARV, with selectivity indices (SI) up to 13738. Studies of mechanisms of action, including time-of-addition experiments and molecular modeling, have shown that these compounds can target the conserved protein p37, which plays a key role in the envelope of the virus. Furthermore, bioinformatic analysis revealed potential interactions with late-stage replication proteins encoded by the A39R and C8L genes. The synthesized derivatives showed activity higher than that of Cidofovir, although they were less effective than that of Tecovirimate. This work highlights the potential of oxadiazolone-based scaffolds as broad-spectrum antipoxviral agents that meet the unmet need for therapy against emerging and re-emerging orthopoxviral threats.