Clarifying the influence of Nb and V microalloying on the ultra-high strength hot stamping steel (UHSHSS) and exploring appropriate process parameters are the basis for effectively regulating properties of the final product. In this study, the effects of different austenitizing temperatures and holding times on the phase transitions, grain sizes and mechanical properties of 22MnB5NbV with Nb and V alloyed are studied by using JMatPro thermodynamic calculations and experiments. By comparing with 22MnB5 without Nb and V alloyed, the effects of Nb and V elements on quenching microstructures, grain sizes and mechanical properties of UHSHSS are analyzed. The suitable austenitizing process parameters of 22MnB5NbV have been obtained. The results show that the grain size of Nb-V-alloyed UHSHSS grows with the increase in the austenitizing temperature and holding time. The 22MnB5NbV steel can be completely austenitized while the austenitizing temperatures ≥870 °C and holding time ≥3 min. Combined with the actual production process, the best austenitizing temperature and holding time are 930 °C and 3 min. Under these conditions, the average grain size is 7.7 μm, the tensile strength, elongation and strength-ductility product are 1570.8 MPa, 6.6% and 10.4 GPa·%, respectively. With the addition of Nb and V elements, the nanoscale precipitates lead to the refinement of the quenched structure and grain size, and the comprehensive properties of UHSHSS have been effectively promoted, in which the elongation and strong-plastic products are increased by ~0.6% and ~1.2 GPa·%, respectively.