The development of renewable woods for power generation can help improve the energy efficiency of buildings, and promote the concept design and implementation of “smart buildings”. Here, with specific chemical treatment and hydrothermal synthesis, we demonstrated the practical value of natural wood for thermoelectric power generation in smart buildings. The prepared wood-based thermoelectric sponges show high Seebeck coefficients of 320.5 and 436.6 μV/K in the vertical and parallel directions of the longitudinal channel of wood. After 500 cycles of the compressive strain at 20%, the corresponding Seebeck coefficients increase up to 413.4 and 502.1 μV/K, respectively, which is attributed to the improved contact and connection between tellurium thermoelectric nanowires. The Seebeck coefficients are much larger than those of most reported inorganic thermoelectric materials. Meanwhile, the thermoelectric sponges maintain excellent thermoelectric and mechanical stability. We further modeled the application value of wood-based thermoelectric sponges in smart buildings for power generation. Relatively high thermoelectric electricity can be obtained, such as in Beijing with over 1.5 million kWh every year, demonstrating the great potential in thermal energy harvest and energy supply.