Both of thallium (Tl) and antimony (Sb) are toxic elements in the natural environment. Emerging Tl and Sb pollution in water has gradually gained public concerns globally. However, limited technologies are available for co-removal of Tl and Sb from wastewater. Herein, an novel system was successfully fabricated to enhance the synergetic removal of both Tl and Sb in wastewater. In this study, MnFeO-biochar composite (MFBC) facilely synthesized by a one-pot hydrothermal method was used as adsorbent and persulfate (PS) activator for simultaneously removing Tl and Sb from wastewater. The optimal reaction conditions for best removal efficiency of Tl and Sb simultaneously were obtained by using the response surface design combined with Box-Behnken Design (BBD) model. Results unveiled that the average removal rates of Tl and Sb can achieve 98.33% and 89.14%, respectively under the optimal reaction conditions. Electron Spin Resonance (ESR), and radical quenching experiments showed that OH and SO play a critical role in the removal of Tl-Sb compound pollution. Via using different characterization, it is revealed that the mechanism of removing Tl-Sb containing wastewater by MFBC-1.4/PS system is oxidation, adsorption, complexation and ion exchange. All these results indicate that MFBC-1.4/PS technology is prospective in highly effective removal of Tl and Sb from wastewater simultaneously.