<p>The aim of the present study was to develop and optimize dual delivery of ascorbic acid and piperine-loaded bilosomes (ASA-PP BLs) to obtain a synergistic immunomodulatory, antioxidant activities, improved stability and permeability. Molecular docking simulation investigations were conducted on ligand binding region of TNF-α and IgE, using ASA and PP as the subjects. ASA-PP BLs were prepared by thin-film hydration technique and optimizing via response surface methodology. Optimized formulation was characterized for particle size, PDI, zeta potential and %EE. TEM, in vitro drug release, ex vivo intestinal permeation and CLSM were employed to assess morphology and permeability. DPPH assay and J744 cell line studies evaluated antioxidant and synergistic effects. In silico investigation showed a substantial affinity between ASA and PP with TNF-α and IgE. Optimized ASA-PP BLs showed a vesicle size of 220.9 ± 2.43&#xa0;nm, PDI of 0.21 ± 0.01, a zeta potential of − 27.48 ± 1.2&#xa0;mV, and %EE of 85.76 ± 1.92% and 87.16 ± 1.80% for ASA and PP, respectively. TEM confirmed spherical, uniform vesicles. In vitro release of drugs in PBS (pH 6.8) was determined to be 80.90 ± 1.68% and 86.47 ± 0.88% of ASA and PP, while intestinal permeation studies demonstrated a 1.82-fold and 1.85-fold higher in gut permeation with ASA-PP BLs compared with neat ASA and PP suspension, respectively. Ex vivo permeation and CLSM experiments indicated improved intestinal drug permeability of ASA-PP BLs, with flux values of 20.93 and 17.08&#xa0;μg/cm²/h. DPPH assay confirmed antioxidant potential, while J774 macrophage cell line showed cell viability and synergistic impact of drugs combination (CI &lt; 1). ASA-PP BLs enhanced drug stability, permeability and antioxidant capacity, suggesting their potential as an effective nanocarrier system for immune modulation.</p> Graphical Abstract <p></p>