Introduction Optimal radiofrequency‐generated thermal energy applications have not been established for hot balloon ablation (HBA) systems. We investigated the feasibility of real‐time monitoring of pulmonary vein (PV) potentials and optimal time‐to‐isolation (TTI)‐guided application strategies in HBAs. Methods and Results Real‐time monitoring of PV potentials was performed using a four‐electrode unidirectional catheter in 34 consecutive patients. Acute isolation was achieved when PV potentials disappeared during HBAs and were undetected by high‐resolution mapping. The TTI, the difference between TTI and the time to reach target temperature (TTRT), and ablation time after isolation were examined for 177 applications in 136 PVs. Real‐time monitoring of PV activity was obtained in 167 out of 177 applications (94.3%) and acute isolation was achieved in 97 out of 177 (54.8%) applications. TTI‐TTRT was significantly shorter, and ablation times after isolation were significantly longer in the acute isolation group than in the other groups. TTI‐TTRT <4.5 seconds and TTIs <33.5 seconds predicted acute isolation (sensitivity 74.2%, specificity 88.4%; sensitivity 76.3%, specificity 76.7%, respectively). Ablation time after isolation >148.5 seconds (sensitivity 93.6%, specificity 51.7%) and >120.5 seconds (sensitivity 84.0%, specificity 78.6%) predicted acute isolation in superior PVs and inferior PVs, respectively. Conclusions Real‐time assessment of PV isolation can be achieved during HBAs with single‐shot techniques. (TTI‐TTRT)s <4.5 seconds and TTIs <33.5 seconds predicted for acute isolation. Ablation time after isolation >148.5 seconds in superior PVs and >120.5 seconds in inferior PVs were effective application durations.