Plants adaptively change their cell wall composition and structure during growth, development, and interactions with environmental stresses. Dirigent proteins (DIRs) contribute to environmental adaptations by dynamically reorganizing the cell wall and/or by generating defense compounds. We established that maize DIR ZmDRR206 (DISEASE RESISTANCE RESPONSE206) mediates maize seedling growth and disease resistance response by coordinately regulating biosynthesis of cell wall components for cell wall integrity (CWI) maintenance. ZmDRR206 responded to pathogen infection by rapidly increasing its expression. Both mutation and overexpression of ZmDRR206 resulted in similar small kernel and diminished seedling growth; while ZmDRR206-overexpression increased disease resistance, greater drought tolerance and reduced photosynthetic activity, thus caused maize seedlings to show a growth-defense trade-off phenotype. Consistently, ZmDRR206-overexpression reduced the contents of primary metabolites and down-regulated the photosynthesis-related genes; while increased the contents of major cell wall components and defense phytohormones; up-regulated defense- and cell wall biosynthesis-related genes in maize seedlings grown under non-stress conditions. Furthermore, ZmDRR206 physically interacted with ZmCesA10, a secondary cell wall-specific cellulose synthase catalytic subunit, in yeast and in planta. Our findings unravel a mechanism that ZmDRR206 maintains CWI during maize seedling growth, providing opportunities for breeding strong disease resistance in maize.