TiO2 nanotube array intercalated anode (Ti/TNAs*/PbO2) was successfully fabricated by anodic oxidation of Ti sheet and electro-deposition of PbO2. The Ti/TNAs*/PbO2 anode was demonstrated high electrochemical activity for the degradation of fluoxetine (FLX) in water. In the batch experiment, 97.2% FLX was removed in 10 min, and the microbial toxicity of FLX solution towards Vibrio fischeri decreased from 41.2% to 2.2% in 30 min. The impressive performance of Ti/TNAs*/PbO2 is attributed to the optimized electronic transport perpendicular to the anode, and the enhanced hydroxyl radical (.OH) yield induced by modified PbO2 crystal face growth. FLX molecular is underwent a mass attack by .OH, and rapidly mineralized to CO2 and H2O. The degradation mechanism of FLX was verified by the analyses of mass spectrometry, electron spin resonance (ESR) spectrometry, and electrochemical measure. A sequential process combined pre-concentration with electrochemical oxidation using Ti/TNAs*/PbO2 anode was set up for the treatment of FLX contaminated simulated wastewater. During continuously 120 h experiment, the removal efficiencies of FLX and TOC remained as high as 94.3% and 83.1%, and the microbial toxicity was disappeared in the effluent all the time.