Polycaprolactone nanoparticles (PCL NPs) were produced by a liquid nonsolvent nanoprecipitation process in a flow-focusing microfluidic device and optimized in terms of particle size, polydispersity index (PDI), and zeta potential zeta. The effects of flow rate ratio (FRR), total flow rate (TFR), the organic solvents tetrahydrofuran and dimethylformamide (DMF), the surfactants polyvinyl alcohol and Tween 80, and polymer molecular weight on the size, PDI, and zeta of PCL NPs were investigated. A stability study was performed to compare the effect of the surfactants on the characteristics of PCL NPs over 7 d. The smallest particles are produced at the highest FRR, TFR, and polymer molecular weight and lowest polymer concentration in DMF. The presence of both surfactants results in smaller NPs.