Worldwide, cardiovascular diseases (CVDs) represent one of the main causes of morbidity and mortality, and acute coronary syndromes are responsible for a large number of sudden cardiac deaths. One of the main challenges that still exist in this area is represented by the early detection and targeted monitoring of the pathophysiology involved in CVDs. During the last couple of years, researchers have highlighted the importance of molecular and epigenetic mechanisms involved in the initiation and augmentation of CVDs, culminating in their most severe form represented by acute myocardial infarction. One of the most studied molecular factors involved in this type of pathology is represented by nuclear transcription factor kappa B (NF-κB), as well as the involvement of microRNAs (miRNAs). It has been suggested that miRNAs can also be involved in the complex process of atheromatous plaque vulnerabilization that leads to an acute cardiac event. In this review paper, we describe the most important molecular mechanisms involved in the pathogenesis of CVDs and atheromatous plaque progression and vulnerabilization, which include molecular mechanisms dependent on NF-κB. For this paper, we used international databases (PubMed and Scopus). The keywords used for the search were “miRNAs biomarkers”, “miRNAs in cardiovascular disease”, “NF-κB in cardiovascular disease”, “molecular mechanism in cardiovascular disease”, and “myocardial NF-κB mechanisms”. Numerous molecular reactions that have NF-κB as a trigger are involved in the pathogenesis of CVDs. Moreover, miRNAs play an important role in initiating and aggravating certain segments of CVDs. Therefore, miRNAs can be used as biomarkers for early evaluation of CVDs. Furthermore, in the future, miRNAs could be used as a targeted molecular therapy in order to block certain mechanisms responsible for inducing CVDs and leading to acute cardiovascular events.