When manufacturing large shafts with multi-specification and small-batch production, both the conventional forging and rolling process bring a high tooling cost due to heavy forging press or large-size specialized roller. In this study, a novel flexible skew rolling (FSR) process is proposed by adding degrees of freedom to the rollers as compared to the typical skew rolling process. Since each of the FSR rollers has three degrees of freedom (circle rotating, radial rotating and radial feeding), the FSR process can be divided into four stages: radial rolling, rollers inclining, skew rolling and rollers levelling. Therefore, the FSR process can produce various shafts with same rollers via programming different movements. To verify the feasibility of FSR process, a physical investigation corresponding with a numerical simulation for a single-step shaft is undertaken with a Φ80×390 mm C45 steel billet. According to the results from physical experiments and numerical simulations, the FSR formed shaft has a maximum deviation of 0.99 mm, and its microstructure and properties have been improved obviously. Moreover, although there is a tendency of center crack in FSR products as predicted by numerical results, both the transverse and longitudinal section of the physical shaft are free from central cracking. The major forming defects existed on the rolled shaft are knurled pockmarks, surface threads and side cavity, which are the typical defects of the conventional skew rolling and cross-wedge rolling and can be removed by machining. To the authors’ knowledge, this novel process has a good combination of flexible production and less loading, which will be of great engineering significance to reduce the tooling cost in large shafts manufacturing.