The deformation mechanism and life prediction model of titanium alloy laser-arc hybrid welded joint during fatigue were studied. At the relatively small maximum cyclic stresses σmax (310 MPa to 350 MPa), the fatigue cracks initiated at the interface of lamellar α′ and needle-like α′ around the pore. At σmax=370MPa, the elongated lamellar α′ around the pore promoted fatigue crack propagation, leading to the formation of secondary cracks. At σmax=390MPa, the formation of two fatigue crack initiation locations and the occurrence of secondary cracks led to the maximum fatigue damage and the minimum fatigue life. In addition, the plastic deformation mainly occurred in β at σmax=310MPa, and it transformed into the phase interface of secondary α-β and granular β-α′ at σmax=350MPa. At σmax=390MPa, the main deformation forms were the cross-slip in β and the dislocations entanglement in α′. Finally, the fatigue life prediction model was established based on the equivalent cyclic stress, and the predicted fatigue life fell within a 3-fold error band.