Spin transition (ST) compounds have been extensively studied because of the changes in rich physicochemical properties accompanying the ST process. The study of ST mainly focuses on the temperature-induced spin transition (TIST). To further understand the ST, we explore the pressure response behavior of TIST and pressure-induced spin transition (PIST) of the 2D Hofmann-type ST compounds [Fe(Isoq)2M(CN)4] (Isoq-M) (M = Pt, Pd, Isoq = isoquinoline). The TISTs of both Isoq-Pt and Isoq-Pd compounds exhibit anomalous pressure response, where the transition temperature (T1/2) exhibits a nonlinear pressure dependence and the hysteresis width (ΔT1/2) exhibits a nonmonotonic behavior with pressure, by the synergistic influence of the intermolecular interaction and the distortion of the octahedral coordination environment. And the distortion of the octahedra under critical pressures may be the common behavior of 2D Hofmann-type ST compounds. Moreover, ΔT1/2 is increased compared with that before compression because of the partial irreversibility of structural distortion after decompression. At room temperature, both compounds exhibit completely reversible PIST. Because of the greater change in mechanical properties before and after ST, Isoq-Pt exhibits a more abrupt ST than Isoq-Pd. In addition, it is found that the hydrostatic properties of the pressure transfer medium (PTM) significantly affect the PIST due to their influence on spin-domain formation.