The oral route of drug administration is usually preferred among the other routes due to ease of administration. Problems arise when hydrophobic drug is formulated for oral administration. Active Pharmaceutical Ingredients (API) having deprived water solubility placed great challenges because of slow as well as reduced dissolution followed by undesirable oral bioavailability. Pharmaceutical scientists worked a lot for developing new formulation strategies to solve the hydrophobic drugs related issues reported previously. Current study is being designed to fabricate nanoparticles of Silibinin and Berberine for boosting their oral bioavailability. Nanoparticles of Silibinin and Berberine were fabricated via two different techniques (Anti-Solvent Precipitation with a Syringe Pump and Evaporative Precipitation of Nanosuspension) using nano-template engineering technology. Propylene glycol was used as stabilizer. Ethanol was used for solvent phase preparation while for anti-solvent phase, water and n-hexane containing Propylene glycol were utilized. Optimization of experimental conditions like stabilizer concentration, solvent-anti-solvent ratios and stirring speed resulted in variety of results for particle size and their related polydispersity index. Evaporative Precipitation of Nanosuspension (EPN) technique was employed for fabrication of Silibinin and Berberine nanoparticles. Silibinin and Berberine nanoparticles demonstrated particle size of 60.23 ± 2.5 nm and 71.53 ± 1.8 nm, PDI 0.217 ± 0.01 and 0.236 ± 0.01 and Zeta potential -35.49 mV and -34.17 mV. Anti Solvent Precipitation with a Syringe Pump (APSP) method was also used for the preparation of Silibinin and Berberine nanoparticles. Silibinin and Berberine nanoparticles showed particle size 104.52 ± 3.2 nm and 102.62 ± 2.8 nm, PDI 0.301 ± 0.02 and 0.284 ± 0.03 and Zeta potential -37.23 mV and -35.27 mV. XI The acquired nano formulations were characterized by using a variety of analytical techniques. The micrographs obtained through Scanning Electron Microscopy (SEM) confirmed the nanometric size particles that appeared identical and spherical in shape. These micrographs revealed the authenticity of the data obtained through Dynamic Light Scattering (DLS) analysis. Powdered X-Ray Diffractometer and Differential Scanning Calorimetry revealed the reduction in the crystallinity of the acquired nanoparticles. No drugs-excipients interaction was found in Fourier Transform Infrared Spectroscopy analysis. The obtained nanoparticles exhibited higher in vitro dissolution and solubility compared to the un-processed drugs. Nano formulations of Silibinin and berberine stored at different temperature according to International Conference on Harmonization (ICH) guidelines revealed optimum stability in the context of particle size and related polydispersity index. Nanoparticles obtained by vacuum drying were filled into the empty capsule shells accordingly. In vivo bioavailability studies revealed that nano formulations exhibit multiple folds better pharmacokinetic parameters as compared to the un-processed drug. As compared to un-processed drug, SB-APSP showed 15.56 and 6.88-folds increase in AUC0→24 and Cmax, whereas, for SB-EPN the said parameters were 18.48 and 7.14 folds increased respectively. Cmax and AUC0→24 for BB-APSP were 3.97 and 3.88 folds higher, whereas, for BB-EPN the said parameters were 4.17 and 3.89 folds greater as compared to the un-processed drug. The findings of the hepatoprotective studies revealed much better and improved results for both Silibinin and berberine in their nanoform in comparison to the un-processed form. The Liver Function Test (LFT) enzymes and Histopathological investigations depicted improved condition of liver when treated with nanoparticles compared to that of un-processed form of the same drug. The same trend for both Silibinin and berberine nanoparticles was XII observed in the anticancer studies. Primary brain tumor cells were exposed to both un processed drug and their respective nanoparticles. The nanoparticles of Silibinin and Berberine further showed comparatively improved antimicrobial, cytotoxic and antioxidant activities compared to the un-processed drug. To summarize, the fabricated nanoparticles of Silibinin and Berberine produced much better and improved results in comparison to the un-processed drug. The nano form of both drugs produced much better and significantly improved oral bioavailability along with pharmacological profile when compared to the un processed drug.