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• Ultrasound assisted microfluidic nanoprecipitation techniques used as a process intensification. • One factor at a time was introduced for parameter screening. • Response surface methodology was introduced for multi-response optimization. • In-vitro release study was performed to analyze the enhancement of drug dissolution rate. Febuxostat (FEB) nanoparticles with the use of poloxamer 407 were prepared using ultrasound assisted microfluidic nanoprecipitation method to enhance febuxostat's solubility and bioavailability. The optimization for this purpose was conducted using the Box Behnken design (BBD) approach. Four factors and three level BBD was used to study the interactive and individual effect of ultrasonic frequency (X 1), amplitude (X 2), Ultrasound assisted microfluidic reactor (USMR) temperature (X 3), and micromixer confluence angle (X 4) on selected two responses. Particle size (Y 1) and encapsulation efficiency (% EE) (Y 2) were the desired responses. The formulated FEB nanoparticles were analyzed by Fourier Transform Infrared Spectroscopy (FTIR) and Transmission Electron Microscopy (TEM). The minimum nanoparticle size, 7.156 nm with 0.22 polydispersity index (PDI) was attained for FEB-loaded polymer nano-sized particles. To investigate the drug release rate (% DR), fast-dissolving tablets of raw FEB and optimized FEB formulation were prepared. A 1.25-fold improvement in FEB solubility rate was experimentally achieved compared to raw FEB. No chemical interaction between the drug and polymer was observed using FTIR. Optimized FEB formulation showed a 92.94 % release rate of the drug in 90 min with 91.70 % EE. [Display omitted] [ABSTRACT FROM AUTHOR]