The aim of the present investigation was to formulate tapentadol hydrochloride-loaded chitosan nanoparticles (CS-NPs) for nose to brain delivery. Chitosan nanoparticles were prepared using ionotropic gelation technique. Optimisation of the formulation and process parameters was done using Box-Behnken Design. The entrapment efficiency, drug loading, Z-average size and zeta potential of the optimised batch were 63.49 +/- 1.61%, 17.25 +/- 1.38%w/w, 201.2 +/- 1.5nm and +49.3mV, respectively. In-vitro release study showed 84.04 +/- 1.53% drug release after 28h, while ex vivo studies indicated higher permeation of CS-NPs through nasal mucosa. The nanoparticles exhibited good mucoadhesiveness, haemocompatibility and safety as evidenced by histopathology. The results of the pharmacodynamic study revealed prolongation of the analgesic activity. The intranasal instillation of CS-NPs resulted in the higher concentrations in brain compared to the drug solution and intravenous administration of CS-NPs. In a nutshell, intranasal administration of tapentadol hydrochloride-loaded CS-NPs is a promising approach for effective pain management.