Refractory high-entropy alloys (RHEAs) show potential for use in extreme environments, such as advanced nuclear reactors, owing to their high melting temperature, and often outstanding combinations of mechanical properties, corrosion resistance, and irradiation-damage tolerance. This study evaluates the fracture toughness of a TiZrNbHfTa RHEA across different scales and microstructures, with a focus on the impact of He2+-ion irradiation. Micro- and millimeter-scale specimens with nanocrystalline (NC) microstructures are compared to existing ASTM standard sized coarse-grained (CG) specimen data, with critical dimensions spanning over three orders of magnitude, from 10 μm to 12 mm. The ASTM standard sized CG specimens exhibit a fracture toughness 41-fold greater than their NC microscale counterparts (210–5.1 MPa m1/2), while NC millimeter-scale specimens show a 7.5-fold higher fracture toughness than NC microscale specimens (38.1–5.1 MPa m1/2). He2+-ion irradiation leads to a 27% decrease in fracture toughness in the NC microscale specimens. The results highlight the impact of sample dimensional scale, microstructure, and ion irradiation on the fracture toughness of the RHEA, indicating a need for thorough examination of such factors when investigating the mechanical properties of these materials.