<p>Silymarin (SLM) and curcuminoids (CURs) are polyphenolic compounds utilized in large doses to manage liver-related diseases. However, it has poor oral bioavailability because of modest solubility, first-pass metabolism, poor dissolution, and poor permeation.. Therefore, double-loaded phytosomal soft nanoparticles (SC PSNPs) were synthesized to increase the solubility, dissolution, bioavailability, and synergistic hepatoprotective performance of SLM and CURs. SC PSNPs were synthesized via bulk co-loading and optimized via Box–Behnken design. SC PSNPs were physically and functionally tested via Fourier-transform infrared spectroscopy, differential scanning calorimetry, powder X-ray diffractometry, solubility, in vivo antioxidant activity, and oral bioavailability. SC PSNPs enhanced the entrapment efficiencies of SLM and CURs by ~ 92.45% and 90.53% w/w, respectively. The SC PSNPs are spherical with a particle size of ~ 356&#xa0;nm, a high zeta potential of − 35.1&#xa0;mV, and a lower PDI value of ~ 0.22, suggesting its suitability for oral use. Characterization studies confirmed the formation of SC PSNPs. The SC PSNPs increased the water solubility of SLM (~ 3-fold) and CURs (~ 54-fold) compared with pure SLM and CURs. SC PSNPs enhanced the dissolution of SLM and CURs by 73% and 90%, compared with pure SLM and CURs. The SC PSNPs restored the elevated in vivo marker enzymes and provided hepatoprotection to the liver. The SC PSNPs improved the oral bioavailability of SLM and CURs by enhancing their <i>Cmax</i>,<i> Tmax</i>,<i> AUC</i>_<i>0–t</i>,<i> t</i>_<i>1/2</i>, and <i>MRT</i>. The development of double-loaded SC PSNPs using the bulk co-loading technique could lead to the emergence of promising dual drug nanocarriers for managing liver-related diseases.</p> Graphical Abstract <p></p>