Purpose <p>Alpha lipoic acid (ALA) is a natural compound that has recently gained attention for its anti-inflammatory potential. ALA has a low bioavailability and in vitro stability, making its clinical use a challenge. Lipid–polymer hybrid nanoparticles (LPHNPs), a newly discovered core-shell nanostructures, are derived from liposomes and polymeric nanoparticles, and they were commonly used to improve in vivo efficiency and stability of active substances.</p> Methods <p>The current study aimed to prepare ALA-loaded LPHNPs via the design of experiments (DoE) approach to improve oral bioavailability and in vitro stability of ALA. The Plackett-Burman design was used to select independent variables by evaluating the effects of drug amount, stirring rate, polymer amount, lipid/polymer ratio, water/organic solvent (W/Os) ratio, and polyvinyl alcohol (PVA) concentration on formulation properties. Afterward, statistically significant formulation parameters were optimized using the Box-Behnken design (BBD). Finally, the in vitro properties were evaluated, and the <i>in vivo</i> anti-inflammatory effect of the optimized formulation was tested using formalin-induced paw edema in mice.</p> Results <p>The main factors affecting the mean particle size (mPS), polydispersity index (PdI), and ζ potential (ZP) values of ALA-loaded LPHNPs were the stirring rate, W/Os ratio, and PVA concentration; however, the independent variables had no significant effect on encapsulation efficiency (EE). Furthermore, optimized ALA-loaded LPHNPs also significantly reduced paw edema thickness and volume with a prolonged duration of action compared to ALA solution during 6&#xa0;h after formalin administration.</p> Conclusion <p>The optimized ALA-loaded LPHNPs with core-shell structure had sustained control release up to day 17 and exhibited superior colloidal and chemical stability under various in vitro conditions and prolonged and robust in vivo anti-inflammatory effect.</p> Graphical Abstract <p></p>