Defect activation is of fundamental importance for plastic deformation. However, its mechanism is not yet fully disclosed in metallic glasses (MGs), especially for those with high configurational entropy that demonstrate outstanding physical or chemical properties, more particularly, mechanical characteristics. In this work, multi-scale defects activation of three rare-earth-based MGs with low-, medium-, and high-entropy (LE, ME, and HE) were systematically investigated by tracing their room-temperature nanoindentation behaviors. Among the three alloys, the Gd18.33Tb18.33Dy18.34Co17.5Al27.5 HE MG exhibits the highest hardness and elastic modulus. Unlike the poor deformability of the LE MG, the pronounced nanoindentation displacements under a constant load were observed in HE and ME MGs, especially at high loading rates. To reveal the plastic origin of HE MGs, a generalized physical model (so-called Maxwell-Voigt) was utilized to describe the nanoindentation deformation on the mesoscale. The characteristic relaxation spectra show that the activated defects with longer relaxation time are mainly responsible for the large nanoindentation displacement at high strain rates. Based on the cooperative shearing model, the shear transformation zone (STZ) volume is determined to be around 0.45–2.98 nm3. The statistics of the short-range order indicate that the HE MG possesses a highly ordered configuration, which results in the difficulty of STZ activation for requiring overcoming a high energy barrier, and a high elastic modulus of the HE MG. Our work might provide insight into the underlying plastic deformation mechanism of HE MGs from the characteristics of activated defects as well as their entropy effect.