Background Poor aqueous solubility limits the clinical use of many drugs, including Tegoprazan (TPZ), a BCS class II compound. Semi-solid dispersions (SSD) using lipid-based excipients such as Gelucire 44/14 (G44) and Labrasol (LB), which possess self-emulsifying properties, have emerged as effective strategies to improve dissolution and oral bioavailability. Methods Binary/ternary phase studies assessed G44 and LB compatibility. A 3² factorial design optimized G44:LB and drug-to-lipid ratios using solubility and particle size as responses. Optimized SSD was formulated into orally disintegrating tablets (ODTs) and evaluated for disintegration, dissolution, solid-state behavior, and in vivo pharmacokinetics in rats. Results The optimized SSD enhanced solubility and nanodispersion. The selected ODT rapidly disintegrated (30 s) with high dissolution (>95% at 180 min). Solid-state analysis confirmed loss of  TPZ crystallinity and amorphous stabilization, improving dissolution and bioavailability. Pharmacokinetic study showed a 1.5-fold increase in AUC versus raw TPZ. Conclusion A G44/LB-based SSD incorporated into ODTs effectively enhanced solubility, dissolution, and oral bioavailability of TPZ. The rapid disintegration and superior release profile of the ODT, combined with the self-emulsifying nature of these lipids, highlight this system as a promising platform for the delivery of poorly soluble drugs.