This study reports the optimization of the preparation of etoricoxib (ETX)-loaded low molecular weight of chitosan (LMWC) nanoparticles (ETX-LMWC-NPs) by ionic gelation method with sodium tripolyphosphate (TPP) as cross-linking agent. The independent variables (LMWC/TPP mass ratio, LMWC, and poloxamer 188 concentration) were formulated and optimized using response surface methodology (RSM) Box-Behnken design (BBD) with three levels for each factor. Size of particles, polydispersity index (PDI), and encapsulation efficiency was investigated as the dependent variable. ETX-LMWC-NPs were characterized by particle size analyzer, scanning electron microscope, UV-Vis spectrophotometry, and Fourier transforms infrared spectroscopy. The ETX-LMWC-NPs have an average particle size of 259.91 nm, a PDI of 0.041, and encapsulation efficiency of 51.25%. ETX-LMWC-NPs are spherical and have a spectrum at wavenumber 1656 cm-1 and 718 cm-1, respectively, indicating the presence of C=N and C-Cl originating from the ETX compound. The ETX release profile at pH 1.2 and 6.8 mediums approach the Korsmeyer-Peppas model. ETX released pH 1.2 did not differ significantly from free ETX with a maximum 10-12% release. ETX release at pH 6.8 had a maximum release of 21% and showed a 19% increase in dissolution rate than free ETX. The ETX-LMWC-CSNPs prepared by optimum formula (2.65 % LMWC, 5.5 LMWC/TPP mass ratio, and 1 mg/mL) showed stable monodispersity nanoparticles and easily soluble in water.