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 was performed to analyze differentially expressed genes (DEGs) in the roots. The results showed that 588, 686, and 1107 DEGs were identified in the 1:1, 1:2, and 2:1 treatment groups, respectively, with the proportion of downregulated genes higher than that of upregulated genes in all groups. DEGs were significantly enriched in 50 pathways, categorized into 5 major classes including cellular processes and environmental information processing. Among these, the plant hormone signal transduction pathway showed the highest enrichment level across all treatments. The auxin-induced protein gene MELO3C013403 and auxin response factor gene MELO3C004381 were significantly upregulated in the 2:1 treatment group, making them potential candidate genes for saline-alkali tolerance. In contrast, photosynthesis-antenna protein genes (e.g., MELO3C021567) were significantly downregulated under the high-salt ratio (2:1) treatment. RT-PCR validation confirmed that the expression levels of these three candidate genes were consistent with the transcriptomic data. Therefore, melon may respond to saline-alkali stress by regulating plant hormone signal transduction, photosynthesis, and carbon metabolism pathways. This study provides candidate genes and a theoretical basis for the genetic improvement of saline-alkali-tolerant melon cultivars.