The mechanical and thermal properties of cryogels depend on their microstructure. In this study, the microstructure of hydroxypropyl methylcellulose (HPMC) cryogels was modified by the addition of ionic (bis (2-ethylhexyl) sodium sulfosuccinate, AOT) and non-ionic (Kolliphor® EL) surfactants to the precursor hydrogels (30 g/L). The surfactant concentrations varied from 0.2 mmol/L to 3.0 mmol/L. All of the hydrogels presented viscous behavior (G″ > G′). Hydrogels containing AOT (c > 2.0 mmol/L) led to cryogels with the lowest compressive modulus (13 ± 1 kPa), the highest specific surface area (2.31 m2/g), the lowest thermal conductivity (0.030 W/(m·°C)), and less hygroscopic walls. The addition of Kolliphor® EL to the hydrogels yielded the stiffest cryogels (320 ± 32 kPa) with the lowest specific surface area (1.11 m2/g) and the highest thermal conductivity (0.055 W/(m·°C)). Density functional theory (DFT) calculations indicated an interaction energy of −31.8 kcal/mol due to the interaction between the AOT sulfonate group and the HPMC hydroxyl group and the hydrogen bond between the AOT carbonyl group and the HPMC hydroxyl group. The interaction energy between the HPMC hydroxyl group and the Kolliphor® EL hydroxyl group was calculated as −7.91 kcal/mol. A model was proposed to describe the effects of AOT or Kolliphor® EL on the microstructures and the mechanical/thermal properties of HPMC cryogels.