Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe mucocutaneous disorders characterized by extensive tissue necrosis; they are often accompanied by severe ocular complications (SOC). The regulatory role of microRNAs (miRNAs) in modulating immune responses in SJS/TEN is not fully understood, particularly in relation to chronic SOC. We explored the expression profiles of specific miRNAs and their potential impact on the regulation of key innate immune genes in patients with SJS/TEN with SOC. We analyzed plasma samples from 100 patients with chronic stage SJS/TEN with SOC and 92 healthy controls to examine the expression levels of eight specific miRNAs (let-7a-5p, let-7d-3p, let-7e-5p, miR-146a-5p, miR-130a-3p, miR-151a-3p, miR-151a-5p, miR-27b-3p) using quantitative RT-PCR (RT-qPCR). In addition, we subjected mononuclear cells from 12 SJS/TEN patients and 9 controls to RT-qPCR to assess the expression of the innate immune-related genes IFI44L, TNFSF10, AIM2, RSAD2, CXCL10, TRIM22, IFI27, and IFIT2. Significant upregulation of 4 miRNAs (let-7a-5p, let-7e-5p, miR-146a-5p, and miR-27b-3p) was observed in the plasma of SJS/TEN patients; this correlated with the increased expression of TLR3, RIG-I, and MDA5. Furthermore, MDA5, IFI44L, RSAD2, CXCL10, and IFIT2 were also significantly up-regulated in the mononuclear cells from these patients, indicating a systemic modulation of immune response genes. Our findings demonstrate that specific miRNAs are up-regulated in SJS/TEN with SOC and associated with the upregulation of critical immune response genes, suggesting their involvement in the pathogenesis and persistence of SOC. These miRNAs and their target genes may serve as potential biomarkers or therapeutic targets in managing SJS/TEN with SOC.