Objective <p>The present research work entails the systematic formulation of nanostructured lipid carriers (NLCs) for the controlled release of mycophenolate mofetil (MMF), a BCS Class II immunosuppressant. The effects of process parameters (homogenization speed, sonication time, homogenization time) and material attributes (concentrations of solid lipid, liquid lipid, emulsifier, and surfactant) on the prepared MMF-NLCs were analyzed.</p> Significance <p>MMF therapy is limited by severe gastrointestinal adverse effects. Efficient MMF delivery requires alleviating these constraints through encapsulation in a stable nanocarrier system.</p> Method <p>1% MMF-NLCs were prepared through the melt emulsification-ultrasonication method. A quality by design (QbD) approach was applied, with Ishikawa fishbone and Taguchi design used for preliminary screening and the central composite design was employed to analyse the effects of process and material parameters. ANOVA and regression analysis were performed to determine statistical significance.</p> Result <p>The optimized formulation was stable, with 230.3 ± 28.6&#xa0;nm particle size, -29.8 ± 2.3mv zeta potential, and 96.07 ± 1.65% entrapment efficiency. The NLCs showed 91.72 ± 0.39% cumulative drug release, with diffusion-erosion controlled kinetics sustained for up to 17&#xa0;h.</p> Conclusion <p>This work suggests a potentially suitable drug delivery system for MMF, offering extended release, reduced dosage frequency, and improved post-transplantation quality of life. However, these clinical benefits require confirmatory in vivo studies.</p> Graphical abstract <p></p>