Background: Soil salinity is one of the major abiotic stress factors that affect crop growth and yield, which seriously restricts the sustainable development of agriculture. Quinoa is considered as one of the most promising crops in the future for its high nutrition value and strong adaptability to extreme weather and soil conditions. However, the molecular mechanisms underlying the adaptive response to salinity stress of quinoa remain poorly understood. To identify candidate genes related to salt tolerance, we performed reference-guided assembly and compared the gene expression in roots treated with 300 mM NaCl for 0, 0.5, 2, and 24 h of two contrasting quinoa genotypes differing in salt tolerance.Results: The salt-tolerant (ST) genotype displayed higher seed germination rate and plant survival rate, and stronger seedling growth potential as well than the salt-sensitive (SS) genotype under salt stress. An average of 38,510,203 high-quality clean reads were generated. Significant Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were identified to deeper understand the differential response. Transcriptome analysis indicated that salt-responsive genes in quinoa were mainly related to biosynthesis of secondary metabolites, alpha-Linolenic acid metabolism, plant hormone signal transduction, and metabolic pathways. Moreover, several pathways were significantly enriched amongst the differentially expressed genes (DEGs) in ST genotypes, such as phenylpropanoid biosynthesis, plant-pathogen interaction, isoquinoline alkaloid biosynthesis, and tyrosine metabolism. 117 DEGs were common to various stages of both genotypes, identified as core salt-responsive genes, including some transcription factor members, like MYB, WRKY and NAC, and some plant hormone signal transduction related genes, like PYL, PP2C and TIFY10A, which play an important role in the adaptation to salt conditions of this species. The expression patterns of 21 DEGs were detected by quantitative real-time PCR (qRT-PCR) and confirmed the reliability of the RNA-Seq results. Conclusions: We identified candidate genes involved in salt tolerance in quinoa, as well as some DEGs exclusively expressed in ST genotype. The DEGs common to both genotypes under salt stress may be the key genes for quinoa to adapt to salinity environment. These candidate genes regulate salt tolerance primarily by participating in reactive oxygen species (ROS) scavenging system, protein kinases biosynthesis, plant hormone signal transduction and other important biological processes. These findings provide theoretical basis for further understanding the regulation mechanism underlying salt tolerance network of quinoa, as well establish foundation for improving its tolerance to salinity in future breeding programs.