Tissue-mimicking materials (TMM) are often used as surrogates for human tissue when developing prospective treatments such as thermal ablation of tumors. Localized heating or ablation may be applied by methods including high-intensity focused ultrasound (HIFU), radio frequency (RF), microwave, and laser treatment. In such methods, confining the heated region to a narrow target is an important concern for minimizing collateral damage to surrounding healthy tissue. Mechanical compression can potentially assist in confining heat near a target region by constricting microvascular blood flow. However, characterization of the effects of compression on thermal properties of the tissue itself (apart from microvasculature) is needed for accurate modeling of heat transfer. Accordingly this study presents a method and material characterization results that quantify the extent to which mechanical compression alters thermal conductivity, specific heat capacity, and thermal diffusivity of a polyacrylamide-based TMM. Cylindrical test specimens were cast from polyacrylamide material with diameter of 50 mm and height of 45 mm. Compression was applied using custom apparatus for applying prescribed uniaxial displacement, with a modular configuration for testing under ambient temperature as well as on a hot plate. Compression force at room temperature was measured with a load cell that was positioned in-line between compression plates. Prescribed heat flux was delivered based on power input, as quantified with the use of a reference sample in a thermal resistance network. Temperature was measured by an array of thermocouples. Software simulations were performed using finite element analysis (FEA) for structural deformation and computational fluid dynamics (CFD) for heat transfer under the combined effects of conduction and convection. The simulations provided estimates of deformed shape and thermal losses that were compared to experimental measurements. Mechanical stress-strain tests using three TMM replicate specimens at room temperature showed a linear stress-strain relationship from approximately 2% to 14% strain and a compressive modulus of elasticity ranging from 7.56 kPa to 12.7 kPa. Distributed temperature measurements under an imposed heat flux resulted in thermal conductivity between 0.89 W/(m·K) and 1.04 W/(m·K), specific heat capacity between 5590 J/(kg·K) and 6720 J/(kg·K) and thermal diffusivity between 1.29 × 10−7 m 2 /s to 1.71 × 10−7 m2/ s. Viscoelastic effects were observed to reach steady state after approximately 20 seconds, with full elastic recovery upon unloading. Thermal conductivity and thermal diffusivity were observed to decrease under mechanical compression, while specific heat capacity was observed to increase. The results affirm that thermal properties of tissue-mimicking material can be altered by mechanical compression. These findings can be applied to future investigation of temperature distribution during localized ablation by methods such as HIFU, and can be extended to refined material modeling of perfused tissue under compression.