Cadmium (Cd)-contaminated soil has been receiving increasing attention worldwide due to the great harm it causes via food-chain enrichment through crops such as wheat. However, there is little research regarding the effects of mannose (MAN) on plants in response to Cd stress. Hence, hydroponic and potted soil experiments were conducted to investigate the mitigation effects of MAN on wheat under Cd stress and the possible mechanism. Compared with Cd treatment alone, foliar spraying of 160 μM MAN significantly reduced the Cd accumulation in shoots and increased the Cd retention in roots. The content of hemicellulose was increased by MAN treatment, and the proportion of Cd retained by hemicellulose in the cell wall of roots was increased. Furthermore, 160 μM MAN significantly reduced the water-extracted and ethanol-extracted Cd in roots, which are easily transported to shoots. In potted soil experiments using Cd-contaminated soil, MAN reduced the Cd content in wheat grain by 26.3%, compared with the control. These findings indicate that foliar spraying of 160 μM MAN resulted in less Cd being transported from roots to shoots by increasing the Cd retention in the cell wall and changing the Cd chemical forms in roots, which promoted wheat growth and reduced the Cd concentration in wheat grain.