Abstract: As global demand for lithium resources continues to grow, achieving the efficient and selective separation of spodumene from associated gangue minerals has become a critical challenge in mineral processing. Conventional collectors generally have poor selectivity and high environmental impact, highlighting the urgent need for green and highly efficient flotation reagents. Based on density functional theory (DFT) and molecular orbital theory, a novel amide−based spodumene collector was systematically designed using molecular simulation methods in this study. Ten polar functional groups were evaluated based on Mulliken charge distribution, frontier orbital energy gap, and chemical adsorption energy. Among them, the −CONH₂ (carbamoyl) group exhibited the most favorable electron−donating characteristics. Subsequently, various alkyl chain lengths and auxiliary groups were introduced to optimize the hydrophobic segment, identifying the dodecyl chain as the optimal hydrophobic moiety. The final target molecule, N−(2−hydroxyethyl)dodecanamide (HEDA), was thus selected. Simulation results showed that HEDA exhibited the lowest adsorption energy (−796.738 kJ/mol) and favorable electronic activity, indicating strong and selective adsorption affinity toward spodumene surfaces. Single mineral flotation tests confirmed the simulation findings. Without the use of any metal ion activators, HEDA achieved a spodumene recovery of 70% at pH 9, while the recovery of albite remained below 20%, demonstrating excellent selectivity. In contrast, sodium oleate yielded recoveries of 46.5% for spodumene and 36.3% for albite under identical conditions, demonstrating inferior selectivity. These results indicate that HEDA enables high−selectivity flotation of spodumene under simplified process conditions. This provides a theoretical basis and experimental evidence for developing green and efficient collectors.