The effects of water content and compression level on tissue thermal conductivity were studied. These effects are important in electrosurgery, as tissue is subjected to both compression and thermal heating. Ex vivo canine spleen tissue was used in this study. A thermal diffusion probe technique was employed to measure the tissue thermal conductivity in three different conditions. First, the tissue thermal conductivity with different water content levels was measured. The measured thermal conductivity decreased as the percentage of water within the tissue decreased. Second, the tissue thermal conductivity under compression, up to 77%, was measured and it showed a 9% reduction as the load was applied. Third, desiccated tissue was compressed, and the thermal conductivity was measured. The compression effect on thermal conductivity was less prominent in the desiccated tissue because less water was squeezed out due to compression. A three-phase Maxwell–Eucken model was developed to predict the tissue thermal conductivity for varying water content and compression levels. The model used the ratio of air, tissue fiber, and water to predict the thermal conductivity and showed a good agreement with the experimental data.