Nitrogen (N) and phosphorus are essential nutrients, and often the most critical yield-limiting factors in wheat production. The increasing global population and the negative effects of N and P fertilizers to the environment challenge wheat breeding to maximize yield potential in an economically and environmentally friendly manner. RAN-seq, QTL mapping, and genome-wide association study (GWAS) were employed to identify genetic loci and genes for efficiency N and P use under different N and P supply conditions in wheat. We cloned genes controlling N assimilation, phosphate homeostasis and cytokinin metabolism, and leaf senescence, and explored their elite alleles. Marker-assisted selection (MAS) and gene editing were used to breed wheat with improved N and P use efficiency. The N and P-efficient wheat lines had significantly higher grain yield than the commercial wheat cultivars under different N and P supply conditions by increasing spike number and grain number per spike.