This investigation explores the use of methoxy polyethylene glycol (mPEG) functionalised poly(D, L-lactide-co-glycolide) (PLGA) nanocrystals of flutamide (FLT) with enhanced solubility, bioavailability and blood circulation time for targeting prostate cancer. FLT had Log P 3.27, short half life 5-6 h, low water solubility, permeability and bioavailability with extensive first-pass metabolism. FLT-loaded nanocrystals were prepared using nanoprecipitation method with surface coating by mPEG and characterised through differential scanning calorimetry, Fourier transform infrared spectroscopy, X-ray powder diffraction, scanning electronic microscopy, particle size, zeta potential, percent entrapment efficiency (% EE), in vitro dissolution, haemolysis, sterility, bioavailability and stability studies. The percent cumulative drug release and % EE of optimised formulation was found to be 95.21 +/- 1.18 and 88.36 +/- 1.20, respectively, for 48 h. In addition, FLT-loaded PEGylated PLGA nanocrystals exhibited significantly delayed blood clearance with drug level of about 766.71 ng/mL at 48 h. In conclusion, PEGylated PLGA FLT nanocrystals could be demonstrated as a novel approach to enhance solubility, bioavailability and blood circulation time.