In this paper, we conceive a novel pillar-structured surface for enhancing nucleate boiling heat transfer, namely a pillar-structured surface with distributed wettability-modified regions on the top of each pillar. A three-dimensional thermal multiphase lattice Boltzmann model with liquid–vapor phase change is employed to investigate the boiling performance on the pillar-structured surface with distributed wettability-modified regions and the associated mechanism of nucleate boiling heat transfer enhancement. According to the distribution of the wettability-modified regions, the bubble dynamics on the newly conceived pillar-structured surface can be classified into three regimes, i.e., regimes I, II, and III, among which the regime II shows relatively better boiling performance than the other two regimes due to the synergistic effects of surface structure and mixed wettability. It is found that in the regime II the bubbles nucleated at the wettability-modified regions do not coalesce with each other, which therefore elongates the length of the triple-phase contact lines on the pillar top in comparison with the pillar-structured surface with a unified wettability-modified region. Meanwhile, in the regime II the bubbles on the pillar top receive a strong bubble-wake effect supplied by the bubbles generated at the bottom substrate, which shortens the bubble growth cycle and promotes the departure of the bubbles on the pillar top, and also reduces the area of dry spots on the pillar top. The influences of the pillar width and the width of the wettability-modified regions are also studied. It is shown that the best boiling performance is always achieved in the cases that fall into the regime II.