Non-coding RNAs (ncRNAs), generated from nonprotein coding DNA sequences, constitute 98-99% of the human genome. Non-coding RNAs encompass diverse functional classes, including microRNAs, small interfering RNAs, PIWI-interacting RNAs, small nuclear RNAs, small nucleolar RNAs, and long non-coding RNAs. With critical involvement in gene expression and regulation across various biological and physiopathological contexts, such as neuronal disorders, immune responses, cardiovascular diseases, and cancer, non-coding RNAs are emerging as disease biomarkers and therapeutic targets. In this review, after providing an overview of non-coding RNAs' role in cell homeostasis, we illustrate the potential and the challenges of state-of-the-art computational methods exploited to study non-coding RNAs biogenesis, function, and modulation. This can be done by directly targeting them with small molecules or by altering their expression by targeting the cellular engines underlying their biosynthesis. Drawing from applications, also taken from our work, we showcase the significance and role of computer simulations in uncovering fundamental facets of ncRNA mechanisms and modulation. This information may set the basis to advance gene modulation tools and therapeutic strategies to address unmet medical needs.