This study focused on the development of an improved formulation screening and optimization method for a self-microemulsifying drug delivery system (SMEDDS). Solubility study and construction of a ternary phase diagram were carried out to determine the primary formulation components. Experimental design combined with a desirability study was employed to obtain the optimal formulation composition. The obtained bufalin SMEDDS formulation was Maisine 35-1 and Miglyol 812N (1 : 1, w/w) of 29.5%, Cremophor EL of 39.5%, and Transcutol P of 30.5%. It showed desired properties with droplet size of 33.9 nm; polydispersity index of 0.126; equilibrium solubility of 12.6 mg/ml, and 73.6% of soluble drug post-digestion. A rapid release of up to 21% occurred in the first 10 min. A bufalin SMEDDS was well absorbed at all intestinal segments. The absorption of bufalin from a SMEDDS was 2.38-fold higher than that of bufalin suspension in terms of relative bioavailability. The studies on solubility and ternary phase diagrams combined with experimental design may offer a valuable and efficient strategy for developing and optimizing a SMEDDS to obtain optimal formulations with desired characteristics.