Nucleation is the formation of a new phase that has the ability to irreversibly and spontaneously grow into a large-sized nucleus within the body of a metastable parent phase. In this experimental work, the effect of wettability on the incipiation of vacuum-driven bubble nucleation, boiling, and the consequent rate of evaporative cooling are studied. One hydrophilic (untreated), and three hydrophobic (chlorinated polydimethylsiloxane, chlorinated fluoroalkylmethylsiloxane and (heptadecafluoro-1,1,2,2-tetrahydrodecyl)triethoxysilane) glass vials of different wettabilities were filled with degassed deionized water and exposed to a controlled vacuum inside a transparent desiccator. The vacuum was increased by 34 mbar abs. (1 inHg rel.) steps with 15-min waiting period to observe bubble nucleation. The average onset pressures for gas/vapor bubble nucleation in CM, CF, and HT vials were 911 ± 30, 911 ± 34, and 925 ± 17 mbar abs., respectively. Bubble nucleation was not observed in hydrophilic vial even at 65 mbar abs. pressure. During the vacuum boiling at 65 mbar abs., the average temperatures of water in hydrophilic, CM, CF, and HT vials reduced from room temperature (~22.5 °C) to 15.2 ± 0.9, 13.1 ± 0.9, 12.9 ± 0.5, and 11.2 ± 0.3 °C, respectively. The results of this study show that the wettability of the container surface has a strong influence on the onset vacuum for vapor/gas bubble nucleation, rate of vacuum boiling, and evaporative cooling. These findings are expected to be useful to develop wettability-based vacuum boiling technologies.