Purpose: Several hydrophilic and hydrophobic approaches have been developed to prevent food debris and plaque accumulation on the denture surface. In this study, we evaluated the possibility of developing a high-functioning self-cleaning denture. Materials and Methods: Denture base resin specimens were divided into the following groups based on the type of surface treatment: control (no treatment); hydrophilic (UV irradiation or tribochemical coating); and hydrophobic (plasma chemical vapor deposition, CVD). Surface analyses were conducted using X-ray photoelectron spectroscopy, Fourier transform infrared spectroscopy, and atomic force microscopy. Physical strength was evaluated using the three point bending test. Data were analyzed using one-way analysis of variance followed by multiple comparisons. Results: The self-cleaning effects of the hydrophilic treatments were unsatisfactory; alternatively, the hydrophobicity, mechanical properties, and self-cleansing ability of the CVD specimens were significantly high (p < 0.05). Conclusion: Hydrophobic surface modifications effectively improved the water repelling properties of the resin without compromising its mechanical properties.