Seeds of the pseudograin, quinoa (Chenopodium quinoa), must be washed extensively prior to consumption to remove saponins that taste bitter. To reduce costs associated with saponin removal, low saponin (sweet) cultivars have been developed. Quinoa is usually tolerant of viral pathogens and is often a local lesion host. However, there is a lack of knowledge on the role of small RNAs in this tolerance. To fill this gap, an experiment was conducted on quinoa with different seed saponin content: sweet ‘Jesse’, medium ‘QQ74’, and bitter ‘Red Head’. Leaves were mock-inoculated or inoculated with Cucumber mosaic virus (CMV). Leaves, harvested 1 and 4 days post inoculation, were used in small RNASeq library preparation. Raw reads were trimmed and excluded from tRNA, rRNA, and snoRNA. They were then mapped to the quinoa reference genome. Novel and known miRNA were identified by miRDeep2. Differentially expressed miRNA (DE-miR) were detected by DESeq2. Target genes of DE-miR were determined by Target Finder. One mature miRNA, miR168, was significantly different and upregulated. The only significant upregulated target gene was “putative disease resistance gene At3g15700.” Higher expression of miR168 induced elevated regulation of this disease resistant gene during CMV infection. Using this conserved miRNA in breeding program may facilitate enhanced resistance to CMV infection in quinoa cultivars. Additional research on small RNAs mapping to CMV genome is ongoing.