The use of starch, a natural polymeric material, and derivatives thereof is based on its adhesive, thickening, gelling, swelling, and film-forming properties, as well as its ready availability. The objective of this research work is to develop an effective propylated Dioscorea abyssinica starch (PDAS) as a hydrophobic excipient for pharmaceutical applications with a reasonable price. This paper reports on the synthesis, characterization, and in vivo safety evaluation of PDAS. Native Dioscorea abyssinica starch (NDAS) was modified to its propylated form with propionic anhydride and characterized. Crystallinity, morphological structure, thermal behavior, solubility, and safety of PDAS were evaluated using x-ray diffraction, SEM, thermogravimetric, gravimetric, and toxicity studies, respectively. Propionyl content and degree of substitution (DS) of starch increased significantly (p < 0.05) with an increase in reaction time and temperature. Propionyl content and DS of starch increased significantly (p < 0.05) with a decrease in the ratio of starch to pyridine and starch to propionic anhydride in the reaction medium. FTIR spectra of PDAS indicated that hydroxyl groups participated in the propylation reaction. X-ray diffraction results showed that the chemical modification destroyed the crystalline structure of the NDAS. SEM of NDAS showed a rounded shape which became irregular after propylation. Thermogravimetric curves revealed that all the PDAS samples decomposed at higher temperatures than their native counterparts. At higher DS, swelling power and solubility in an aqueous environment significantly (p < 0.05) decreased below that of the native starch. PDAS with high DS, were soluble in organic solvents at room temperature. But PDAS with lower DS didn't dissolve in all types of organic solvents used. PDAS (DS = 2.842) in distilled water did not produce adverse effects in rats. Based on the results obtained, it can be concluded that PDAS can be considered as a generally safe excipient and fulfills the physicochemical properties of a hydrophobic excipient.