Abstract: The combined application of organic and mineral water-soluble fertilizers is a vital measure for developing ecological and efficient agriculture. To investigate the effects of different organic-mineral water-soluble fertilizer combinations on foxtail millet growth and soil environment, this study established six treatments under drip irrigation with equal nitrogen application: seaweed fertilizer + mineral fertilizer (HNK), humic acid fertilizer + mineral fertilizer (FNK), fish protein fertilizer + mineral fertilizer (YNK), mineral fertilizer alone (NK), irrigation only (WCK), and no fertilizer or irrigation (CK). It analyzed their impacts on millet yield, grain quality, water use efficiency (WUE), agronomic fertilizer use efficiency (FUE), soil nutrients, pH, and their interrelationships. Results demonstrated that all three combined treatments (HNK, FNK, and YNK) significantly improved millet yield, quality, water/fertilizer utilization, and soil nutrients compared to NK. The HNK treatment showed optimal performance in enhancing yield, effective panicles, grain weight per panicle, protein content, WUE, and FUE, with yield and FUE increasing by 10.6%-11.5% and 25.8%-26.6%, respectively, compared to the NK. FNK and YNK also effectively increased yield (by 4.6%-6.5%) and WUE while improving grain quality. The significant increase in effective panicles was the key driver of yield advantage in combined treatments over NK. All three combined treatments significantly increased soil organic matter (SOM), total nitrogen, nitrate nitrogen, available phosphorus, and available potassium compared to NK, with SOM showing a notable improvement within two years; HNK effectively enhanced soil nitrate nitrogen and available potassium, while FNK best improved SOM. Soil pH remained more stable under combined treatments, mitigating acidification compared to NK. Correlation analysis revealed that soil available nutrients had a direct effect on yield, with SOM exhibiting a significant positive correlation with yield; grain protein content showed a significant negative correlation with amylose content. A cumulative effect over time was also observed for the improvement of certain millet quality and soil quality parameters under the combined application of organic and inorganic water-soluble fertilizers. Comprehensive evaluation indicates that the HNK combination is the optimal strategy for enhancing foxtail millet yield, efficiency, and soil quality under drip irrigation under the conditions described in this paper.