<p>This study employs an integrated experimental and computational approach to evaluate the performance of mushroom waste (MW)-enhanced clay bricks in hot-arid climate applications. The research methodology combines laboratory characterization of brick specimens (0–15% MW content) with energy performance simulations using Grasshopper and Ladybug tools to assess mechanical, physical, and thermal properties. Experimental investigations quantified key material parameters, including thermal conductivity, compressive strength, and bulk density, while computational modeling evaluated building energy performance under realistic climatic conditions. This dual-method approach enables a comprehensive assessment of both material properties and system-level energy efficiency improvements. Laboratory tests demonstrated that incorporating 15% MW reduced thermal conductivity by 62% (from 0.77 to 0.293 W/m·K) and bulk density by 26% (1922 to 1419 kg/m³) while maintaining compressive strength (8.6 MPa) above structural requirements. Energy simulations revealed that 0.45 m-thick walls with 15% MW content achieved optimal performance, reducing annual cooling loads by 12.4% (140.6 kWh savings in peak summer months). Sensitivity analysis identified cooling setpoint temperature as the most influential factor (SI = 1.02) on energy savings, followed by MW content (SI = 0.79) and wall thickness (SI = 0.61), highlighting the interplay between material properties and occupant behavior. Economic analysis showed a marginal 2% increase in initial costs was offset by 15.3–17.2% annual energy savings, with net present value projections confirming 12.5–15.6% cost reductions over 10 years despite Egypt’s 33.66% inflation rate. The results validate MW-enhanced bricks as a sustainable solution that simultaneously improves building energy performance, utilizes agricultural waste, and remains economically viable, supporting circular economy principles in construction.</p>