The aim of this study was to determine the effects and underlying molecular mechanisms of humic acid (HA) on foxtail millet (Setaria italica Beauv.) under drought conditions. The rainless climate of the Shanxi Province (37°42'N, 112°58'E) in China provides a natural simulation of drought conditions. Two foxtail millet cultivars, Jingu21 and Zhangza10, were cultivated in Shanxi for two consecutive years (2017-2018) based on a split-plot design. Plant growth, grain quality, and mineral elements were analyzed in foxtail millet treated with HA (50, 100, 200, 300, and 400 mg L-1) and those treated with clear water. Transcriptome sequencing followed by bioinformatics analysis was performed on plants in the normal control (CK), drought treatment (D), and drought + HA treatment (DHA) groups. Results were verified using real-time quantitative PCR (RT-qPCR). HA at a concentration of 100-200 mg L-1 caused a significant increase in the yield of foxtail millet and had a positive effect on dry weight and root-shoot ratio. HA also significantly increased P, Fe, Cu, Zn, and Mg content in grains. Moreover, a total of 1098 and 409 differentially expressed genes (DEGs) were identified in group D vs. CK and D vs. DHA, respectively. A protein-protein interaction network and two modules were constructed based on DEGs (such as SETIT_016654mg) between groups D and DHA. These DEGs were mainly enriched in the metabolic pathway. In conclusion, HA (100 mg L-1) was found to promote the growth of foxtail millet under drought conditions. Furthermore, SETIT_016654mg may play a role in the effect of HA on foxtail millet via control of the metabolic pathway. This study lays the foundation for research into the molecular mechanisms that underlie the alleviating effects of HA on foxtail millet under drought conditions.