The present work investigates the feasibility of fabricating chitosan (CS)-levofloxacin (LOF) nanoparticles by ionotropic gelation technology. An orthogonal experiment was designed to optimize its preparing parameters and multi-index comprehensive weighed score analysis method was used to study the effects of various factors including concentration of CS, concentration of tripolyphosphate (TPP), mass ratio of CS to TPP, and mass ratio of CS to LOF on the properties of nanoparticles. The particles prepared under optimal condition of 2mg/ml CS concentration, 2mg/ml TPP concentration, 0.5:1 mass ratio of oil to water and 4:1 mass ratio of CS to TPP had 140nm diameter, 0.95 span, 6.13% loading capacity (LC) and 24.91% encapsulation efficiency (EE). In vitro release profile showed that LOF released fast initially and then slowly with T 90 occurring at 76.5h. Future studies should focus on antibacterial and biocompatible properties in order to evaluate its potential as sustainable delivery system.