Foxtail millet (Setaria italica L.) is a climate-resilient and nutrient-efficient cereal suitable for low-input agricultural systems. Climate change, soil nutrient depletion, and rising input costs have increased interest in such crops for sustainable production. The objective of this chapter is to synthesize physiological, agronomic, and molecular mechanisms governing nutrient use efficiency (NUE) and climate resilience in foxtail millet. The chapter also evaluates its role in strengthening productivity under rainfed and marginal environments. An integrative review approach was adopted using evidence from crop physiology, genomics, agronomy, remote sensing, modeling tools, and field-based case studies. Comparative analyses with major cereals were used to highlight efficiency and resilience advantages. Quantitative results from case studies show that optimized NPK application (30:20:20 kg ha⁻1) improves biomass production and grain yield while maintaining high NUE. Moderate irrigation regimes (120–150 mm) enhance water productivity and root development under stress conditions. DSSAT-based simulations predict yield responses across nitrogen and water gradients with errors generally below 10–15%. Field evaluations further reveal substantial genetic variability in phenology, biomass partitioning, and stress tolerance. Future research should integrate multi-omics-assisted breeding with precision nutrient and water management. Policy and value-chain support are essential to scale foxtail millet adoption in climate-vulnerable regions.