Compared with certain transition metals (e.g., iron, cobalt, and manganese), noble metals are less frequently applied in peroxymonosulfate (PMS)-based advanced oxidation processes (AOPs). Palladium (Pd), as one of noble metals, has been reported to possess the possibility of both radical mechanisms and electron transfer mechanisms in a heterogeneous Pd/PMS system, however, data are still sparse on the homogeneous Pd/PMS system. Therefore, this work aims to explore the homogeneous reactivity of PMS by Pd(II) ions from the aspects of reaction parameters, radical or non-radical oxidation mechanisms, and the relationship between pollutants’ degradation rate and their molecular descriptors based on both experimental data and density functional theory (DFT) calculation results. As a result, the reaction mechanism of Pd(II)/PMS followed a radical-driven oxidation process, where sulfate radicals (SO4•−), rather than hydroxyl radicals (HO•), were the primary reactive oxidant species. BOx and EHOMO played significant roles in pollutant degradation during the Pd(II)/PMS system. It turned out that the bond’s stability and electron donation ability of the target compound was responsible for its degradation performance. This finding provides an insight into PMS activation by a noble metal, which has significant implications for scientific research and technical development.