The influence of twin-zone Joule annealing (TJA) on the microstructure and magnetic properties of melt-extracted Co68.2Fe4.3B15Si12.5 amorphous microwires has been investigated. Experimental results indicated that twin-zone Joule annealing treatment improved the GMI property of as-cast wires to a greater extent comparing with Joule annealing (JA) and conventional vacuum annealing (CVA) techniques. At 15MHz, e.g., the maximum GMI ratio [ΔZ/Z0]max of a TJA wire increases to 104.29%, which is more than 5 times of 20.49% for the as-cast wire, nearly two times of 56.47% for the JA wire, while the CVA wire has a decreased GMI ratio; the field response sensitivity of the TJA wire increased to 171.62%/Oe from 80.32%/Oe for the as-cast wire, exceeding the values of 140.76%/Oe for the JA wire and of 39.17%/Oe for the CVA wire. The stress or structural relaxation in TJA wire increases circumferential permeability, and magnetic moment achieves a critical state of excitation for overcoming eddy-current damping or “nail-sticked” action in rotational magnetization process at relatively high frequency. From the microstructural point of view, the role of regularly arranged atomic micro-regions (RAAM) and of medium range order region (MROR) determines the efficiency of various annealing techniques. Conclusively, TJA is established as an efficient annealing technique to enhance the GMI effect of wires, which can subsequently be used for detecting weak magnetic field at relatively wider working range (±2.0Oe).