This study investigated the fretting wear and fatigue of full-scale railway axles. Fatigue tests were conducted on full-scale railway axles, and the fretting wear and fretting fatigue in the fretted zone of the railway axles were analysed. Three-dimensional finite element models were established based on the experimental results. Then, multi-axial fatigue parameters and a linear elastic fracture mechanics-based approach were used to investigate the fretting fatigue crack initiation and propagation, respectively, in which the role of the fretting wear was taken into account. The experimental and simulated results showed that the fretted zone could be divided into zones I–III according to the surface damage morphologies. Fretting wear alleviated the stress concentration near the wheel seat edge and resulted in a new stress concentration near the worn/unworn boundary in zone II, which greatly promoted the fretting crack initiation at the inner side of the fretted zone. Meanwhile, the stress concentration also increased the equivalent stress intensity factor range ΔKeq below the mating surface, and thus promoted the propagation of fretting fatigue crack. Based on these findings, the effect of the stress redistribution resulting from fretting wear is suggested to be taken into account when evaluating the fretting fatigue in railway axles.