Any derailment in the normal cellular functions can potentially lead to a disease condition. Regulations in the gene expression patterns are kept under tight control to maintain normal cellular functions. In most pathological conditions, cellular mechanisms get either inhibited or enhanced, which leads to the abnormal conditions. The molecular mechanisms that are otherwise in tight control cause induced expression or suppression of specific genes, whose presence or absence causes the observed disease phenotype. In healthy state, these mechanisms show tissue-specific expression patterns. A typical well-characterized molecular signaling pathway that was studied in many different cell types and disease conditions is the JAK-STAT pathway. One of the key findings reported in most cell types when the JAK-STAT pathway gets overexpressed is increased cell proliferation and inflammation. However, in many proliferative disorders, inhibition of JAK-STAT signaling is favored, such as in cardiac hypertrophy or viral infections. Induced expression of JAK-STAT signaling is required for tissue or cell regeneration, such as in spinal cord injuries. Although the molecular intermediates and the downstream effector proteins in the JAK-STAT signaling pathway were well explored, the mechanisms that uniquely regulate the JAK-STAT signaling in each disease appear to be different. In this manuscript, how the JAK-STAT pathway gets uniquely regulated by different microRNAs under different non-cancerous diseases has been reviewed.