Vessel sealing using bipolar electrosurgery is becoming a common practice in modern operating rooms. Despite all the advantages such as faster operation, less bleeding, and shorter postsurgery recovery time, side effects including sticking, charring, and rebleeding still occur, leading to increased surgery time and sometimes fatal complications. Tissue impedance during the electrosurgical process has been used to determine the electrical power of the process. However, little has been done to understand the dynamic tissue impedance and its effectiveness in monitoring the vessel sealing process. Moreover, the samples used in previous studies all had small diameters of 2–5 mm. In this study, an experimental setup was developed to perform vessel sealing tests using large-diameter blood vessel samples with mimicking blood flow. The tissue impedance during the heating process was obtained. Burst pressures after sealing were measured. A finite element simulation model was developed to understand the dynamic impedance behavior. It is seen that the tissue impedance increases rapidly in the beginning of the heating process and remains at a level that is several orders of magnitude higher than the initial value. This rapid impedance increase indicates protein denaturing, thus can be used to monitor the electrosurgical vessel sealing process. An impedance-based monitoring algorithm was developed, with which a burst pressure at least twice the normal human systolic blood pressure was achieved.