Monkeypox is an emerging zoonotic disease recognized as the most important orthopoxvirus infection in humans. On June 23, 2022, the World Health Organization classified the monkeypox virus as a “evolving threat of moderate public health concern” after receiving reports of more than 3000 illnesses in more than 50 countries across five regions. Despite the fact that no particular treatment for monkeypox virus have been approved, studies on animal models have shown that certain antiviral drugs viz., Cidofovir, Acyclovir, Famciclovir, Valacyclovir, and Tecovirimat, are effective against the orthopoxvirus. For Quantitative Structure Activity/Property Relationship (QSAR/QSPR) analysis, topological descriptors are used to represent a molecules’ chemical structure numerically in order to predict the physicochemical and pharmacological properties of new chemical compounds with high degree of precision. The QSPR is a analysis of how a molecules’ properties relate to its chemical structure, and topological descriptor is a key factor in this relationship. A molecular structure is considered as a graph \(G=(V,E)\) , where \(V\) is the set of atoms and \(E\) is the set of bonds between the atoms. In this paper, a new class of vertex-degree based descriptor namely Sombor index (SO) and its variants are investigated for the above antiviral drugs. In the QSPR analysis, the correlation between the ADMET properties and Sombor indices of antiviral drugs are examined through linear regression model. The findings show that the variants of Sombor indices have a substantial relationship with the ADMET properties of the antiviral drugs used to treat monkeypox disease.