Localized rectal delivery is a promising strategy for ulcerative colitis, as it may increase drug exposure at inflamed sites in the distal colorectum while reducing systemic exposure. However, many natural anti-inflammatory small molecules, including β-sitosterol, are hydrophobic and have poor aqueous dispersibility, limiting their formulation and therapeutic use. Conventional rectal dosage forms typically have fixed structures, making it difficult to tailor drug-release behavior. To address these challenges, a β-sitosterol-loaded self-emulsifying lipid suppository was fabricated using semisolid extrusion (SSE) three-dimensional (3D) printing, and the ability of the internal architecture to modulate early in vitro drug release was investigated. The Gelucire® 44/14-based matrix exhibited shear-thinning behavior and temperature-dependent softening, enabling SSE 3D printing. Upon contact with an aqueous medium, the printed suppositories formed submicron dispersions. Liquefaction and self-emulsification times ranged from 18.27 to 24.27 min and from 4.33 to 8.54 min, respectively. A representative formulation had a droplet size of 370.67 ± 39.09 nm and a polydispersity index of 0.27 ± 0.04. Fourier transform infrared, differential scanning calorimetry, and X-ray diffraction analyses indicated good drug–matrix compatibility and reduced β-sitosterol crystallinity, suggesting partial solubilization within the lipid matrix. With the matrix composition and external geometry held constant, in vitro release was adjusted by varying the internal pore architecture and nominal infill density. Lower-infill-density structures promoted faster medium penetration and earlier β-sitosterol release, whereas higher-infill-density structures slowed release by increasing structural resistance and diffusion-path tortuosity. These results demonstrate the feasibility of using SSE 3D printing to produce structure-modulated rectal dosage forms containing poorly water-soluble natural compounds.