How surface wettability affects boiling heat transfer is still a challenging problem at nanoscale. In this work, a three-dimensional analysis of surface potential energy is used to address its relationship to surface wettability and nanoscale pool boiling characteristics of liquid molecules. It is found that the major reason for the enhanced heat transfer by increasing the surface wettability is essentially the improvement of surface potential energy, of which the influence is summarized using logic order. Moreover, the nanoscale boiling of water on copper surfaces with various wettability is investigated, which reveals that the increase in surface wettability can improve the heat transfer coefficient and critical heat flux under high superheat conditions in both nano- and macroscale systems. Besides, the effects of surface potential energy on contact angle, Kapitza resistance, heat transfer coefficient, and critical heat flux are analyzed systematically to demonstrate their relationships. A nondimensional analysis is finally implemented to correlate the normalized surface potential energy (P), the Nusselt number (Nu), and the normalized critical heat flux (J): Nu = 0.081P0.34, J = 0.827P0.50 (P 2.387). This work provides insights into the enhancement mechanisms for the phase-change heat transfer of liquid molecules over surfaces with different wettability.