Introduction: Micronutrient deficiencies, particularly iron (Fe) and zinc (Zn), are prevalent in a large part of the human population across the world, especially in children below 5 years of age and pregnant women in developing countries. Since wheat constitutes a significant proportion of the human diet, improving grain Fe and Zn content in wheat has become important in improving human health.Objective: This study aimed to quantify the effect of foliar application of iron sulfate heptahydrate (FeSO₄.7H₂O) and zinc sulfate heptahydrate (ZnSO₄.7H₂O) and their combination on grain Fe and Zn concentrations, as well as grain protein content (GPC). The study also aimed to assess the utility of these applications in large field conditions.Methods: To address this issue, field experiments were conducted using 10 wheat cultivars and applying a foliar spray of FeSO₄.7H₂O (0.25%) and ZnSO₄.7H₂O (0.50%) separately (@400 L of solution in water per hectare during each spray) and in combination at two different crop growth stages (flowering and milking) for three consecutive crop seasons (2017–2020). The study used a split-plot design with two replications to assess the impact of foliar application on GFeC, GZnC, and GPC. In addition, an experiment was also conducted to assess the effect of soil (basal) @ 25 kg/ha ZnSO₄, foliar @ 2 kg/ha, ZnSO₄.7H₂O (0.50%), and the combination of basal + foliar application of ZnSO₄ on the grain micronutrient content of wheat cultivar WB 02 under large field conditions.Results: GFeC increased by 5.1, 6.1, and 5.9% with foliar applications of FeSO₄, ZnSO₄, and their combination, respectively. GZnC increased by 5.2, 39.6, and 43.8% with foliar applications of FeSO₄, ZnSO₄, and their combination, respectively. DBW 173 recorded the highest increase in GZnC at 56.9% with the combined foliar application of FeSO₄ and ZnSO₄, followed closely by HPBW 01 at 53.0% with the ZnSO₄ foliar application, compared to the control. The GPC increased by 6.8, 4.9, and 3.3% with foliar applications of FeSO₄, ZnSO₄, and their combination, respectively. Large-plot experiments also exhibited a significant positive effect of ZnSO₄ not only on grain Zn (40.3%, p ≤ 0.001) and protein content (p ≤ 0.05) but also on grain yield (p ≤ 0.05) and hectoliter weight (p ≤ 0.01), indicating the suitability of the technology in large field conditions.Conclusion: Cultivars exhibited a slight increase in GFeC with solitary foliar applications of FeSO₄, ZnSO₄, and their combination. In contrast, a significant increase in GZnC was observed with the foliar application of ZnSO₄ and the combined application of FeSO₄ and ZnSO₄. In terms of GPC, the most significant enhancement occurred with the foliar application of FeSO₄, followed by ZnSO₄ and their combination. Data demonstrated the significant effect of foliar application of ZnSO₄ on enhancing GZnC by 39.6%. Large plot experiments also exhibited an increase of 40.3% in GZnC through the foliar application of ZnSO₄, indicating the effectiveness of the technology to be adopted in the farmer’s field.