The extracellular matrix (ECM) creates a multifaceted system for the interaction of diverse structural proteins, matricellular molecules, proteoglycans, hyaluronan, and various glycoproteins that collaborate and bind with each other to produce a bioactive polymer. Alterations in the composition and configuration of ECM elements influence the cellular phenotype, thus participating in the pathogenesis of several human disorders. Recent studies indicate the crucial roles of non-coding RNAs in the modulation of ECM. Several miRNAs such as miR-21, miR-26, miR-19, miR-140, miR-29, miR-30, miR-133 have been dysregulated in disorders that are associated with disruption or breakdown of the ECM. Moreover, expression of MALAT1, PVT1, SRA1, n379519, RMRP, PFL, TUG1, TM1P3, FAS-AS1, PART1, XIST, and expression of other lncRNAs is altered in disorders associated with the modification of ECM components. In the current review, we discuss the role of lncRNAs and miRNAs in the modification of ECM and their relevance with the pathophysiology of human disorders such as cardiac/ lung fibrosis, cardiomyopathy, heart failure, asthma, osteoarthritis, and cancers.