Vessel sealing with a bipolar electrosurgical device has become a common practice in modern operation rooms. Despite all the advantages, such as easier operation, less bleeding, and shorter post-surgery recovery time, side effects including sticking, charring, and rebleeding, often occur, leading to increased operation time and sometimes complications that are potentially fatal. Tissue impedance during the electrosurgical procedure has been used to improve the surgical outcome However, this method has only been effective for small-diameter vessels of 3–5 mm. Overall, little is found in literature on dynamic impedance monitoring of blood vessel sealing using bipolar electrosurgical devices. In this study, an experimental setup was designed and built to perform vessel sealing tests on large-diameter blood vessels with mimicking blood flow. Ex vivo porcine carotid artery samples with a diameter about 7 mm were used. Burst pressures after sealing were measured. It was found that the tissue impedance started with an initial decrease, followed by a rapid increase, and ended with a plateau that was orders of magnitude higher than the initial impedance. The rapid increase of impedance provides indication of protein denaturing, thus the seal completion. This feature was used to monitor the electrosurgical vessel sealing process. It is shown that a burst pressure at least twice the normal human systolic blood pressure can be achieved with heating until the maximum tissue impedance is reached. A FEA model was developed in COMSOL to understand the dynamic impedance behavior in the vessel sealing process.