Polyimide (PI) aerogels possess significant potential for various applications due to their outstanding mechanics and thermal insulation. However, a major drawback of these aerogels is their susceptibility to moisture, which not only compromises their insulative performance but also leads to an increase in weight. To address this issue, we have developed a moisture-resistance technique by incorporating a long-chain hydrophobic barrier at the ortho position relative to the imide groups to enhance the moisture-resistance of the PI aerogels. This approach involved using a series of diamines with hydroxyl groups strategically located at the ortho position of imide groups as reactants. The resulting PI aerogels demonstrated a significant improvement in water resistance, reducing water-uptake to merely one-tenth of that recorded in unmodified samples. Furthermore, the effectiveness of this hydrophobic modification was validated through molecular dynamics simulations, which indicated a diffusion coefficient of 4.41 × 10 m/s after modification. These findings represent a considerable advancement in developing effective methods for hydrophobic modification of PI aerogels, with potential applications in aerospace, electronic communications, and environmental protection.