Abstract Targeting RNA with small molecules is a major challenge of current medicinal chemistry, and the identification and design of original scaffolds able to selectively interact with an RNA target remains difficult. Various approaches have been developed based on classical medicinal chemistry strategies (fragment‐based drug design, dynamic combinatorial chemistry, HTS or DNA‐encoded libraries) as well as on advanced structural biology and biochemistry methodologies (such as X‐ray, cryo‐EM, NMR, or SHAPE). Here, we report the de novo design, synthesis, and biological evaluation of RNA ligands by using a straightforward and sustainable chemistry combined with molecular docking and biochemical and biophysical studies that allowed us to identify a novel pharmacophore for RNA binding. Specifically, we focused on targeting the biogenesis of microRNA‐21, the well‐known oncogene. This led us not only to promising inhibitors but also to a better understanding of the interactions between the small‐molecule compounds and the RNA target paving the way for the rational design of efficient inhibitors with potential anticancer activity.