Purpose <p>The aim of the current study was to improve the bioavailability of a poorly water-soluble drug, lumefantrine, by formulating a ternary solid dispersion.</p> Methods <p>The ternary dispersion of lumefantrine was prepared with tartaric acid and poloxamer by quench cooling. Tartaric acid was used to induce disorder through intermolecular ionic interactions, whilst poloxamer was used to improve the wettability and dissolution performance through micellar solubilization. The dispersions were optimised by employing a design of experiments approach. The prepared ternary dispersions were characterized by DSC, p-XRD, and FTIR.</p> Results <p>High drug loading within the dispersions could be achieved (&gt; 50% w/w) without recrystallization. The ternary dispersions exhibited improved solubility and dissolution performance in biorelevant media. The mechanism of dissolution improvement was thought to be the combination of amorphization and micellar solubilization. Interestingly, ternary dispersion bridged the gap between FaSSIF and FeSSIF dissolution of lumefantrine, which is expected to mitigate the problem of variable bioavailability. Furthermore, the solubility improvement translated into improved bioavailability where Cmax and exposure (AUC) of lumefantrine were enhanced approximately 5-fold from solid dispersions. The anti-plasmodial activity of lumefantrine from the ternary solid dispersions was found intact.</p> Conclusion <p>Therefore, the combination of improved bioavailability and retained anti-plasmodial efficacy in the developed ternary dispersion could potentially enhance the therapeutic effectiveness of lumefantrine-based anti-malarial treatments.</p>