Frequent drought events especially those occur in the reproductive stages severely restrict global crop productivity.  Moderate drought priming during the earlier growth stages is a promising strategy for plants to resist to recurrent severe drought stress.  However, the underlying mechanisms remain unclear.  Here, we subjected wheat plants to drought priming during the vegetative growth stage and to severe drought stress at 10 days after anthesis.  We then collected leaf samples at the ends of the drought priming, recovery periods, and at the ends of drought stress for transcriptome sequencing in combination with phenotypic and physiological determination.  The drought-primed wheat plant maintained a lower plant temperature, with higher stomatal openness and photosynthesis, thereby resulting in much less 1,000-grain weight and grain yield losses under the later drought stress than the non-primed plants.  Interestingly, 416 genes of which 27 transcription factors (e.g., MYB, NAC, HSF) seemed to be closely related to the improved drought tolerance as indicated by the dynamic transcriptome analysis.  Moreover, the candidate genes showed six temporal expression patterns and significantly enriched in several stress response related pathways such as plant hormone signal transduction, starch and sucrose metabolism, arginine and proline metabolism, inositol phosphate metabolism, and wax synthesis.  These findings illustrate new insights into physiological and molecular mechanisms of the long-term effects of early drought priming to effectively improve drought tolerance in wheat, which proved potential approaches to challenge the increasing abiotic stresses and secure food safety under global warming scenarios.