This study explored the effect of combined application of fertilizer, herbicide, and selenium (Se) on the grain quality of foxtail millet in order to optimize the foxtail millet cultivation techniques. ‘Jingu 21’ was used as material, a quadratic general rotation combination design with five factors and five levels was set to study the effects of combined application of nitrogen (N), tetraphosphorus decaoxide (P2O5), potassium oxide (K2O), tribenuron-methyl (TBM) herbicide, and Se on the quality of foxtail millet. Principal component analysis was performed to evaluate the eight quality indicators of foxtail millet, including protein, fat, folate, gel consistency, amylase, alkali digestion value, yellow pigment and selenium. The first principal component, which could explain 58.14% of the total variance of grain quality, was chosen as the comprehensive quality. N×K2O, N×MSF, and K2O×MSF interactions had significance influence on the comprehensive grain quality of ‘Jingu 21’. The recommended cultivation conditions of N, P2O5, K2O, Se and MSF were 109.88 kg/hm2, 99.20 kg/hm2, 110.91 kg/hm2, 87.58 g/hm2, and 419.35 g/hm2 respectively, and the highest predicted comprehensive quality was 57.68. This study provided support for the use of nitrogen, phosphorus, potassium, selenium and herbicide in an optimal combination for foxtail millet production, and provided a theoretical basis for the optimal cultivation management and targeted planting of high-quality foxtail millet.