Drought stress is one of the major abiotic stress factors that affect plant growth and crop productivity. Tartary buckwheat is a nutritionally balanced and flavonoid-rich pseudocereal crop and also has strong adaptability to different adverse environments including drought. However, little is known about its drought tolerance mechanism. In this study, we performed comparative physiological and transcriptomic analyses of two contrasting drought-resistant Tartary buckwheat genotypes under nature drought treatment in the reproductive stage. Under drought stress, the drought-tolerant genotype XZSN had significantly higher contents of relative water, proline, and soluble sugar, as well as lower relative electrolyte leakage in the leaves than the drought-susceptible LK3. A total of 5,058 (2,165 upregulated and 2,893 downregulated) and 5,182 (2,358 upregulated and 2,824 downregulated) potential drought-responsive genes were identified in XZSN and LK3 by transcriptome sequencing analysis, respectively. Among the potential drought-responsive genes of XZSN, 1,206 and 1,274 genes were identified to be potential positive and negative contributors for XZSN having higher drought resistance ability than LK3. Furthermore, 851 out of 1,206 positive drought-resistant genes were further identified to be the core drought-resistant genes of XZSN based on WGCNA analysis, and most of them were induced earlier and quicker by drought stress than those in LK3. Functional annotation of the 851 core drought-resistant genes found that a large number of stress-responsive genes were involved in TFs, abscisic acid (ABA) biosynthesis, signal transduction and response, non-ABA signal molecule biosynthesis, water holding, oxygen species scavenging, osmotic adjustment, cell damage prevention, and so on. Transcriptional regulatory network analyses identified the potential regulators of these drought-resistant functional genes and found that the HD-ZIP and MYB TFs might be the key downstream TFs of drought resistance in Tartary buckwheat. Taken together, these results indicated that the XZSN genotype was more drought-tolerant than the LK3 genotype as evidenced by triggering the rapid and dramatic transcriptional reprogramming of drought-resistant genes to reduce water loss, prevent cell damage, and so on. This research expands our current understanding of the drought tolerance mechanisms of Tartary buckwheat and provides important information for its further drought resistance research and variety breeding.