Cutaneous T cell lymphoma (CTCL) is characterized by a background of chronic inflammation, where malignant CTCL cells escape immune surveillance. To study how microRNAs (miRs) regulate T-cell exhaustion, we performed miR sequencing analysis, qRT-PCR, and in situ hybridization on 45 primary CTCL samples, three healthy skin samples, and CTCL cell lines, identifying miR-155-5p, miR-130b-3p, and miR-21-3p. Moreover, miR-155-5p, miR-130b-3p, and miR-21-3p positively correlated with immune checkpoint gene expression in lesional skin samples and were enriched in the IL-6/Jak/signal transducer and activator of transcription signaling pathway by gene set enrichment analysis. Further gene sequencing analysis showed decreased mRNA expression of the major negative regulators of Jak/signal transducer and activator of transcription signaling: SOCS, PIAS, and PTPN. Transfection of MyLa and HuT78 cells with anti–miR-155-5p, anti‒miR-21-3p, and anti‒miR-130b revealed a considerable increase in SOCS proteins along with a significant decrease in the levels of activated signal transducer and activator of transcription 3 and immune checkpoint surface protein expression as well as decreased cell proliferation. Downregulation of miR-155, miR-130, and miR-21 in CTCL cell lines decreased CTCL cell growth and facilitated CD8⁺ T-cell–mediated cytotoxic activity, with concordant production of IFN-γ and CD107a expression. Our results describe the mechanisms of miR-induced T-cell exhaustion, which provide a foundation for developing synthetic anti-miRs to therapeutically target the tumor microenvironment in CTCL.