•Novel microstructured surfaces were fabricated with spatially-controlled mixed wettability.•Area ratio of hydrophobic region on pillar tops greatly affects the boiling performance of mixed wetting microstructured surfaces.•Synergistic enhancement mechanism was explored by optimally utilizing the combined effects of mixed wettability and microstructures. Surface wettability is a very important factor that affects the pool boiling heat transfer performance and the surfaces with mixed wettability have attracted much attention in recent years for enhancing pool boiling. However, the existing experimental studies were mainly focused on plain surfaces with mixed wettability or microstructured surfaces whose tops of microstructures were entirely subjected to wettability modification. In this work, we fabricated microstructured surfaces with spatially-controlled mixed wettability by controlling the size of the hydrophobic spots on the tops of microstructures. Saturated pool boiling of water on the surfaces was experimentally investigated to explore the synergistic enhancement of pool boiling by optimally utilizing the combined effects of mixed wettability and microstructures. The experimental results indicate that the size of the hydrophobic spots on the tops of microstructures has a significant influence on the boiling performance of microstructured surfaces with mixed wettability. By controlling the size of the hydrophobic spots on the tops of microstructures to optimize the combined effects of mixed wettability and microstructures, the novel microstructured surface performs much better than a base microstructured surface without wettability modification and the one whose tops of pillars are entirely subjected to wettability modification. The heat transfer coefficient (HTC) was found to be significantly enhanced together with a higher critical heat flux (CHF). Specifically, the achieved largest HTC and highest CHF are 257.6 kW/(m2 K) and 2190.8 kW/m2, respectively, which are 4.55 times and 1.87 times, respectively, over those of the plain copper surface.