Proprotein convertase subtilisin/kexin 9 (PCSK9) is responsible for the degradation of the hepatic low-density lipoprotein receptor (LDLR), which in turn regulates the circulating low-density lipoprotein cholesterol (LDL-C) level. For this reason, the PCSK9 inhibition, by small molecules or peptides, is a validated therapeutic approach for fighting hypercholesterolemia and cardiovascular diseases. In this field, we have recently reported an imidazole-based peptidomimetic that has shown PCSK9 inhibitory activity in the micromolar range. Here, by applying advanced computational techniques, the binding mechanism of that imidazole peptidomimetic was predicted. Then, among a small set of poly-imidazole analogs, compounds showing the highest theoretical affinity were suitably synthesized, relying on a van Leusen reaction based multicomponent strategy. One compound (named RIm13) displayed a PCSK9 inhibitory activity 10-fold lower than the template compound, and, remarkably, at a concentration of 1 μM, it successfully prevented the LDLR degradation mediated by PCSK9 on HepG2 cells. As well as increasing the LDL uptake at the same concentration, RIm13 represents currently one of the most potent small molecules targeting the PCSK9/LDLR protein-protein interaction.