We report optimization of geometric and flow parameters affecting size and uniformity of PLGA (poly lacticco-glycolic acid) nanoparticles (NPs) prepared inside a microchannel via nanoprecipitation. The parameters studied were microchannel geometry, flow rate and flow configurations (number of interfaces between water and solvent streams). In addition to the flow rate ratio (FRR), which had the highest impact on particle size and polydispersity, we found that increasing channel aspect ratio (H:W) and number of reacting interfaces significantly reduced particle size (p < 0.0001, p v 0.001, respectively). Careful tuning of microchannel geometry and flow parameters enabled preparation of NPs with diameter down to 65 nm.