High cycle fatigue performance and the microstructures of laser-arc hybrid welded 8 mm-thick heavy plate of AA6082 aluminum alloy were studied firstly. The microstructures and the fatigue fracture surfaces were characterized by scanning electron microscope, electron back-scattered diffraction and transmission electron microscopy. The effects of the microstructures on different fatigue process were discussed theoretically. The fatigue limit at 107 cycles was about 120 MPa, far superior to the corresponding values for pure laser or pure arc welds. The fatigue process consisted of crack initiation and three crack propagation stages. The hybrid welding produced the welds with low percent porosity, grain refinement, and increased static strength. It improved the fatigue life during crack initiation, and then prolonged the total fatigue life. The theoretical analysis suggested that the microstructures played a key role in improving the fatigue properties of hybrid weld.