Cd contamination in rice urgently needs to be addressed. Nano hydroxyapatite (n-HAP) is an eco-friendly material with excellent Cd fixation ability. However, due to its own high reactivity, innovative application of n-HAP in the treatment of Cd contamination in rice is needed. In this study, we proposed a new application, namely n-HAP pre-treatment, which can effectively reduce Cd accumulation in rice and alleviate Cd stress. The results showed that 80 mg/L n-HAP pre-treatment significantly reduced Cd content in rice shoot by 35.1%. Biochemical and combined transcriptomic-proteomic analysis revealed the possible molecular mechanisms by which n-HAP pre-treatment promoted rice growth and reduced Cd accumulation. (1) n-HAP pre-treatment regulated gibberellin and jasmonic acid synthesis-related pathways, increased gibberellin content and decreased jasmonic acid content in rice root, which promoted rice growth; (2) n-HAP pre-treatment up-regulated gene CATA1 expression and down-regulated gene OsGpx1 expression, which increased rice CAT activity and GSH content; (3) n-HAP pre-treatment up-regulated gene OsZIP1 expression and down-regulated gene OsNramp1 expression, which reduced Cd uptake, increased Cd efflux from rice root cells. Cd contamination in rice is an important worldwide environmental concern. The traditional way of using n-HAP to treat Cd contamination has limited efficiency. To achieve reasonable effect, a higher concentration of n-HAP must be used. However, the high concentration of n-HAP may have a negative impact on rice. Therefore, this study proposed n-HAP pre-treatment as a novel way of n-HAP application, which can ensure effective Cd contamination treatment and promote rice growth under low n-HAP dosage. This study provides a new theoretical basis for applying n-HAP in the prevention and control of Cd contamination in rice.