Plant nutrition plays a central role in the global challenge to produce sufficient and nutritious food, lessen rural poverty, and reduce the environmental footprint of crop production. Efficient fertilizer use requires tailored solutions that are scientifically sound, practical and scalable especially for smallholder farmers, such as the crop-led site-specific nutrient management (SSNM) approach developed in the 1990s for cereal production systems in Asia to address variability among farms. Originating from a simple model to calculate crop nutrient requirements, this unique approach has evolved over 25 years, covering a growing number of crops and countries in Asia and Africa with development of digital tools and dissemination approaches. We performed a meta-analysis using 62 published papers across 11 countries to compare SSNM with the farmer fertilizer practice, for rice, wheat and maize. Overall, relative to the farmer practice, grain yield was 0.5 Mg ha-1 (11.8%) greater with SSNM, and this was achieved using about 20 kg N ha-1 less nitrogen fertilizer; associated with greater agronomic nitrogen use efficiency under SSNM than the farmer practice (17 vs 12 kg grain kg-1 N applied). This was likely because SSNM had more splits of nitrogen fertilizer than farmer practice, which was applied in better congruence with key periods of crop growth and nitrogen demand, thereby reducing nitrogen pollution to the environment and sustaining soil health. Moreover, the benefits with SSNM were achieved through balanced nutrition, with application of the same amount of phosphorus but higher potassium rates than farmer practice. In countries where grain yield with the farmer practice was high, a substantial reduction in nitrogen application rate with SSNM resulted in greater improvement of nitrogen use efficiency and reduced nitrogen loss and this was especially the case for China across the three crops. In contrast, larger yield gains were observed for farmers who typically attain low yields than farmers that already have high yields. Such cases were mainly observed in Africa and South Asia. We know no other agronomic intervention that has increased crop yield, profitability, and nitrogen use efficiency across three cereal crops and geographies. This approach represents a win-win situation from which millions of smallholder farmers could benefit, which can be achieved through use of digital decision support tools; integrating policy incentives, financial and input supply services, and improving knowledge exchange among extension, public and private partners.