Particle deposition on the surface of the drying chamber poses the main drawback in the spray drying process, which reduces the product recovery and affects the quality of the product. In view of this, the potential application of chemical surface modification to produce a hydrophobic surface that reduces the powder adhesion (biofouling) on the wall of the drying chamber was investigated in this study. The hydrophobic Polydimethylsiloxane (PDMS) solution was used in the vertical dipping method at room temperature to determine the optimum coating parameters on borosilicate glass and stainless-steel substrates, which were used to mimick the wall surface of the drying chamber, to achieve highly hydrophobic surfaces. A single-factor experiment was used to define the range of the PDMS concentration and treatment duration using the Response Surface Methodology (RSM). The Central Composite Rotatable Design (CCRD) was used to study the effects of the concentration of the PDMS solution (X1, %) and the treatment duration (X2, hr) on the contact angle of the substrate (°), which reflected the hydrophobicity of the surface. A three-dimensional (3D) response surface was constructed to examine the influence of the PDMS concentration and treatment duration on the contact angle readings, which serve as an indicator of the surface's hydrophobic characteristic. Based on the optimisation study, the PDMS coating for the borosilicate glass achieved an optimum contact angle of 99.33° through the combination PDMS concentration: X1 = 1% (w/v) and treatment time X2 = 4.94 hr, while the PDMS coating for the stainless-steel substrate achieved an optimum contact angle of 98.31° with PDMS concentration: X1 = 1% (w/v) and treatment time X2 = 1 hr. Additionally, the infrared spectra identified several new peaks that appeared on the PDMS-treated surfaces, which represented the presence of Si-O-Si, Si-CH3, CH2, and CH3 functional groups for the substrates coated with PDMS. Furthermore, the surface morphology analysis using the Field Emission Scanning Electron Microscopy (FESEM) showed the presence of significant roughness and uniform nanostructure on the surface of PDMS-treated substrates, which indicated the reduction of wettability and the potential effect on unwanted biofouling on the spray drying chamber.