The influence of nodule defects on the characteristics of femtosecond laser-induced damage has not been fully investigated. In this study, two types of 800 nm/1064 nm dual-band HfO2/SiO2 high-reflection films with different configurations were analyzed. Combined with finite-difference time-domain electric field simulation and focused ion beam analysis, the initial state and growth process of femtosecond laser damage of nodules were explored. In particular, the sequence of blister damage determined by the film design and the inner damage caused by nodules were clarified. The rule of the laser-induced damage threshold of different size nodules was obtained. The difference in the damage behavior of nodules in the two types of films was elucidated.