Moisture-proof coating is essential to protect humidity-sensitive optical or electronic components. Generally, the moisture resistance of sol–gel coating depends primarily on the surface chemical composition and the internal microstructure of the coating. In this work, experimental studies were conducted on sol–gel silica coatings with different surface free energy (SFE) and pore volumes to elucidate the effect of the two contributing factors on moisture resistance. The results show that these two factors are both independent and synergistic. As the SFE or pore volume of the coating decreases, the moisture resistance is improved. However, when the SFE is reduced to around 10 mJ/m2, the silica coatings exhibit superior moisture resistance and are independent of the microstructure. Furthermore, once the pore volume of coatings is reduced to approximately 0.5 cc/g, the coatings exhibit notable moisture resistance, regardless of their surface chemical composition. This work provides fundamental insights and valuable recommendations for the design and fabrication of sol–gel moisture-proof coatings, with broad applicability in moisture-sensitive electronic components, photovoltaic cells, and cultural relics protection, among others.