MicroRNAs are a class of non-coding small RNAs involved in negative regulation of gene expression and playing critical roles in developmental and metabolic pathways. Studies in several plants have identified few microRNAs and other small (s) RNAs that target regulators of phenylpropanoid metabolic pathway called MYB transcription factors. However, it is not well-understood how sRNA mediated regulation of MYBs influences accumulation of specific secondary metabolites. Using sRNA-sequencing, degradome analysis, mRNA-seq and proteomic analysis, we establish that grape lines with high anthocyanin content express two abundant MYB-targeting miRNAs resulting in differential expression of specific MYB proteins. miR828 and miR858 target coding sequences of specific helix motifs in the mRNA sequences of MYB proteins. Targeting by miR828, caused MYB RNA decay and production of cascade secondary siRNAs that depend on RNA dependant RNA polymerase 6. MYB suppression and cascade silencing was more robust in grape lines with high anthocyanin content when compared to a flavonol-rich grape line. We establish that miRNA-mediated silencing targeted repressor class of MYBs to promote anthocyanin biosynthesis in grape lines with high anthocyanins. We propose that this process regulates expression of appropriate MYBs in grape lines to produce specific secondary metabolites.