Background: Powder-based 3D printing, an advanced additive manufacturing technique, can produce oral disintegrating tablets (ODTs) without disintegrants, creating larger-pored tablets via layer-by-layer powder stacking for better water absorption than traditional tablets. Methods: This study focused on using powder-based 3D printing to fabricate clozapine-based ODTs. Through central composite design (CCD), the formulation of ODTs was optimized for rapid disintegration. Analytical techniques such as X-ray Powder Diffraction (XRD), Fourier Transform Infrared Spectroscopy (FTIR), and Differential Scanning Calorimetry (DSC) were employed to investigate the compatibility between clozapine and excipients. Results: The optimized 3D-printed ODTs exhibited a remarkably short disintegration time of (9.9 ± 0.7) s compared to (40) s for compressed tablets. The contact angle of the 3D-printed ODTs was measured as 60.48 ± 0.36°, indicating favorable wettability for disintegration. Scanning Electron Microscopy (SEM) analysis revealed a porous structure in 3D-printed tablets, with a porosity of 48.97% (over two times higher than that of compressed tablets as determined by mercury injection meter). Conclusions: Collectively, this finding demonstrates the feasibility of fabricating highly hydrophilic and non-distensible ODTs without disintegrants using powder-based 3D printing.