Plants adaptively change their cell wall composition and structure during their 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. A maize DIR, ZmDRR206, was previously reported to play a dominant role in regulation of storage nutrient accumulation in endosperm during maize kernel development. Here we show that ZmDRR206 mediates maize seedling growth and disease resistance by coordinately regulating biosynthesis of cell wall components for cell-wall integrity (CWI) maintenance. Expression of ZmDRR206 was induced in maize seedlings upon pathogen infection. ZmDRR206 overexpression in maize resulted in reduced seedling growth and photosynthetic activity but increased disease resistance and drought tolerance, revealing a tradeoff between growth and defense. Consistently, ZmDRR206 overexpression reduced the contents of primary metabolites and down-regulated genes involved in photosynthesis, while increasing the contents of major cell wall components, defense phytohormones, and defense metabolites, and up-regulated genes involved in defense and cell-wall biosynthesis in seedlings. ZmDRR206-overexpressing seedlings were resistant to cell-wall stress imposed by isoxaben, and ZmDRR206 physically interacted with ZmCesA10, which is a cellulose synthase unit. Our findings suggest a mechanism by which ZmDRR206 coordinately regulates biosynthesis of cell-wall components for CWI maintenance during maize seedling growth, and might be exploited for breeding strong disease resistance in maize.