Background: Pregabalin, a first-line agent for neuropathic pain, has physicochemical and pharmacokinetic characteristics — high aqueous solubility combined with variable, dose-dependent absorption and a short elimination half-life — that make conventional oral formulations suboptimal for sustained symptom control. Self-nanoemulsifying drug delivery systems (SNEDDS) offer a lipid-based strategy to improve solubilisation, present the drug in a pre-dissolved nanoemulsion state, and modulate release. 
Objective: This study aimed to develop and statistically optimize a pregabalin-loaded liquid SNEDDS (L-SNEDDS) using a Box–Behnken design (BBD) in Design-Expert software and to characterize the optimized formulation. 
Methods: Preformulation studies (solubility, melting point, Fourier-transform infrared [FTIR] compatibility, UV λmax and calibration) were performed. Isopropyl myristate, Tween 80, and PEG 400 were selected as oil, surfactant, and co-surfactant, respectively, following solubility and emulsification-efficiency screening, and their proportions were mapped using a pseudo-ternary phase diagram. A three-factor, three-level BBD (17 runs) was used to optimize the amounts of oil, surfactant, and co-surfactant against self-emulsification time, percentage transmittance, and cloud point. The optimized batch was characterized for pH, viscosity, globule size, polydispersity index (PDI), zeta potential, morphology, drug content, entrapment efficiency, in vitro release, release kinetics, and thermodynamic/dilution stability. 
Results: Quadratic models best described all three responses (p < 0.05, non-significant lack-of-fit). The optimized formulation showed a self-emulsification time of 25.2 s, percentage transmittance of 100.06%, and a cloud point of 84.6 °C, closely matching model predictions. The optimized L-SNEDDS exhibited a mean globule size of 28.2 nm, PDI of 0.324, zeta potential of −3.7 mV, drug content of 109.9% w/w, and entrapment efficiency of 89.47%. in vitro release under simulated gastric conditions reached 78.4% at 60 min and best fitted the Higuchi and Korsmeyer–Peppas models (R² = 0.716 and 0.717, respectively; release exponent n = 0.474), indicating Fickian diffusion-controlled release. The optimized formulation was thermodynamically stable to heating–cooling cycling, centrifugation, freeze–thaw cycling, and serial aqueous dilution. 
Conclusion: Integration of Design-Expert–driven Box–Behnken optimization enabled rational, statistically validated development of a nanoscale, stable pregabalin SNEDDS with favourable in vitro release characteristics, providing a robust liquid intermediate for subsequent solidification into an oral solid dosage form.