This study examines the effects of the spent substrate of oyster mushroom (SMS) for growing wheat at different drought conditions. The SMS not only served as the sole fertilizer to produce normal growth and grain yield of wheat but also improved the soil quality after harvest to raise the soil organic matter, maintain the soil alkalinity and increase field capacity unlike the synthetic fertilizer amendment. Simultaneously, SMS treatment enhanced drought tolerance of wheat by enabling germination at 8.5% soil water content and completing sexual reproduction to grain production even at 6.3% soil water content