The objective of present work was to prepare nanocrystals of Lopinavir (LPN) to enhance its solubility and dissolution rate with aim of dose reduction and minimising the side effects associated with it’s oral administration. Nanocrystals of LPN were prepared by anti-solvent precipitation method using a 32 full factorial design, employing stirring speed (X1) and concentration of surfactant (X2) as independent variables. The nanocrystals obtained were characterised mainly for particle size (PS), zeta potential (ZP), crystallinity, saturation solubility, in vitro dissolution and permeability. Results demonstrated profound effect of concentration of surfactant (pluronic F-68) on both the PS and polydispersity index (PDI) values. The optimised nanocrystals formulation had particle size 265nm, PDI 0.260 and ZP in the range of -18.0 to -22.5mv. X-Ray diffraction studies (XRPD) and Differential scanning calorimetry (DSC) studies suggested nanocrystal formation and absence of crystalline peaks, indicating loss of crystallinity, additionally confirmed by scanning electron microscopy (SEM). Nanocrystals showed 30.45 fold enhancements in aqueous solubility, and 38.5 fold in phosphate buffer pH 6.8, as compared to pure LPN. In vitro release studies have demonstrated 92.20% cumulative drug release within 3 hrs from nanocrystals compared to 42.65% from pure LPN. Even, increase in permeation flux from 423.1 μg/cm2/hr to 632.93 μg/cm2/hr in case of nanocrystals was also indication of enhanced dissolution. Stable LPN nanocrystals formulated by anti-solvent precipitation method shows improved solubility and dissolution. It has been concluded that LPN nanocrystals were obtained with significant improvement in saturation solubility and drug losing it’s crystalline nature when compared with plain drug.