Saline-alkaline stress is an abiotic stress that suppresses rice plant growth and reduces yield. However, few studies have investigated the mechanism by which rice plants respond to saline-alkaline stress at a global transcriptional level. Dongdao-4 and Jigeng-88, which differ in their tolerance to saline-alkaline stress, were used to explore gene expression differences under saline-alkaline stress by RNA-seq technology. In seedlings of Dongdao-4 and Jigeng-88, 3523 and 4066 genes with differential levels of expression were detected, respectively. A total of 799 genes were upregulated in the shoots of both Dongdao-4 and Jigeng-88, while 411 genes were upregulated in the roots of both genotypes. Among the downregulated genes in Dongdao-4 and Jigeng-88, a total of 453 and 372 genes were found in shoots and roots, respectively. Gene ontology (GO) analysis showed that upregulated genes were enriched in several GO terms such as response to stress, response to jasmonic acid, organic acid metabolic process, nicotianamine biosynthetic process, and iron homeostasis. The downregulated genes were enriched in several GO terms, such as photosynthesis and response to reactive oxygen species. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed that Dongdao-4 seedlings were specifically enriched in the biosynthesis of secondary metabolites such as diterpenoids and phenylpropanoids. The upregulated genes that were involved in secondary metabolite biosynthesis, amino acid biosynthesis, betalain biosynthesis, organic acid metabolic process, and iron homeostasis pathways may be central to saline-alkaline tolerance in both rice genotypes. In contrast, the genes involved in the diterpenoid and phenylpropanoid biosynthesis pathways may contribute to the greater tolerance to saline-alkaline stress in Dongdao-4 seedlings than in Jigeng-88. These results suggest that Dongdao-4 was equipped with a more efficient mechanism involved in multiple biological processes to adapt to saline-alkaline stress.