Low-activation body-centered cubic (bcc) multi-principal element alloys (MPEAs) are promising structural materials for nuclear power plants to ensure good radiation resistance and safe operation in service. Accordingly, a novel bcc MPEAs family consisting of only low-activation elements was proposed in this study. Machine learning and lab experiments were combined to explore an empirical criterion for rapidly discovering the relationship between composition and compression ductility. It was found that Pugh’s ratio (κ) and valence electron concentration (VEC) are two key attributes to identify the target alloys. Leveraging this criterion, an alloy with a satisfactory combination of ultimate tensile strength (832 MPa) and fracture strain (17.2%) at the typical service temperatures in terms of nuclear structural materials was determined. It kept bcc single-phase while deforming. The effects of tensile temperature and strain rate on the mechanical property were also discussed, respectively. Our results are a step forward in the exploration and design of high-performance low-activation bcc MPEAs in the field of nuclear application.