4,6,4′-trimethylangelicin (TMA) is a promising pharmacological option for the treatment of cystic fibrosis (CF) due to its triple-acting behavior toward the function of the CF transmembrane conductance regulator. It is a poorly water-soluble drug, and thus it is a candidate for developing a self-emulsifying formulation (SEDDS). This study aimed to develop a SEDDS to improve the oral bioavailability of TMA. Excipients were selected on the basis of solubility studies. Polyoxyl-35 castor oil (Cremophor^® EL) was proposed as surfactant, diethylene glycol-monoethyl ether (Transcutol^® HP) as cosolvent, and a mixture of long-chainmono-,di-, and triglycerides (Maisine^® CC) or medium-chain triglycerides (Labrafac^TM lipophile) as oil phases. Different mixtures were prepared and characterized by measuring the emulsification time, drop size, and polydispersity index to identify the most promising formulation. Two formulations containing 50% surfactant (w/w), 40% cosolvent (w/w), and 10% oil (w/w) (Maisine^® CC or Labrafac^TM lipophile) were selected. The results showed that both formulations were able to self-emulsify, producing nanoemulsions with a drop size range of 20–25 nm, and in vivo pharmacokinetic studies demonstrated that they were able to significantly increase the oral bioavailability of TMA. In conclusion, SEEDS are useful tools to ameliorate the pharmacokinetic profile of TMA and could represent a strategy to improve the therapeutic management of CF.