To decipher the molecular response mechanism of melon to saline-alkali stress, seedlings of the melon cultivar ‘Xikaixin’ were treated with 50 mmol·L⁻¹ mixed solutions of NaCl and NaHCO₃ at ratios of 1:1, 1:2, and 2:1 to simulate saline-alkali stress. Transcriptome sequencing of roots yielded 78.98 Gb of clean data (≥6.02 Gb per sample) with Q30 ≥96.61% and genome alignment rates of 97.00%-98.02%, identifying 588, 686, and 1107 differentially expressed genes (DEGs) in the 1:1, 1:2, and 2:1 groups, respectively. DEGs were significantly enriched in 50 pathways categorized into 5 major classes, with the plant hormone signal transduction pathway showing the highest enrichment across all treatments. A key original finding is the distinct balance shift between auxin and ABA: two auxin-related genes (auxin-induced protein gene MELO3C013403 and auxin response factor gene MELO3C004381) were specifically upregulated (≥2-fold vs. control) in the high-salt 2:1 group, while ABA-related genes were upregulated and auxin/jasmonic acid/gibberellin-related genes were downregulated in the 1:2 group, indicating a cultivar-specific hormone balance modulation in ‘Xikaixin’ under saline-alkali stress. In contrast, photosynthesis-antenna protein genes (e.g., MELO3C021567) were significantly downregulated (to 32% of the control) under the 2:1 treatment. RT-PCR validation confirmed the consistency of these candidate genes’ expression with transcriptomic data. Therefore, melon may respond to saline-alkali stress by regulating the plant hormone signal transduction (especially Auxin-ABA balance), photosynthesis, and carbon metabolism pathways. This study provides novel candidate genes and a theoretical basis for the genetic improvement of saline-alkali-tolerant melon cultivars, with the unique Auxin-ABA balance modulation as a key original contribution.