Proprotein convertase subtilisin/kexin type 9 (PCSK9), one of the key regulators of the low-density lipoprotein receptor (LDLR), can play a direct role in atheroma development. Although advances in the understandings of geneticPCSK9polymorphisms have enabled to reveal the role ofPCSK9in the complex pathophysiology of cardiovascular diseases (CVDs), increasing lines of evidence support non-cholesterol-related processes mediated by PCSK9. Owing to major improvements in mass spectrometry-based technologies, multimarker proteomic and lipidomic panels hold the promise to identify novel lipids and proteins potentially related to PCSK9. Within this context, this narrative review aims to provide an overview of the most significant proteomics and lipidomics studies related to PCSK9 effects beyond cholesterol lowering. These approaches have enabled to unveil non-common targets of PCSK9, potentially leading to the development of novel statistical models for CVD risk prediction. Finally, in the era of precision medicine, we have reported the impact of PCSK9 on extracellular vesicles (EVs) composition, an effect that could contribute to an increased prothrombotic status in CVD patients. The possibility to modulate EVs release and cargo could help counteract the development and progression of the atherosclerotic process.