Abstract: Dipine drugs, classified as dihydropyridine calcium channel antagonists, are widely utilized in clinical settings as antihypertensive vasodilator calcium antagonist to treat angina pectoris, hypertension, and coronary artery diseases. Commonly used dipine drugs, including felodipine, amlodipine besylate, and nifedipine, can effectively regulate blood pressure levels, increase blood flow to the heart and blood vessels, and thus aid in reducing blood pressure. Additionally, dipine drugs have been used in treatment for Alzheimer’s disease and are known to provide protective effect on the liver. Understanding the fragmentation pathways during mass spectrometry ionization is crucial for studying their metabolic pathways. In this study, the fragmentation behaviors of felodipine, amlodipine besylate, and nifedipine were investigated using electrospray ionization-mass spectrometry coupled to collision-induced dissociation (ESI-CID-MS/MS). Through detailed analysis, the fragmentation characteristics of these dipine drugs were elucidated. It was observed that common reactions under the target ion mode include dehydrogenation, proton migration, dehydration, and the loss of branched chain groups. A key finding of this study is the dehydroaromatization process during the fragmentation of dipine drugs. In this process, the fragment ions generated through dehydroaromatization can serve as characteristic diagnostic markers for identifying dipine drugs. Under the high-energy conditions, dipine molecules undergo complex rearrangements, leading to the conversion of saturated carbon-carbon bonds into unsaturated aromatic ring structures. This transformation alters the chemical properties of the drug molecules and represents the primary fragmentation pathway of dipine drugs. Moreover, dehydroaromatization offers valuable insights into the in vivo metabolic conversion of these drugs, which may occur under the influence of drug-metabolizing enzymes. This conversion can potentially affect both the efficacy and safety of dipine drugs, highlighting the importance of understanding this process for therapeutic use. This study not only provides a method for identifying fragment ions but also establishes a theoretical framework for comprehending the fragmentation pathways of dipine drugs.