As an important structural material for automotive lightweight, the higher hydrogen embrittlement sensitivity of ultra-high-strength hot stamping steel (UHSHSS) is an important factor limiting the development. In this work, Nb-V alloying of traditional 22MnB5 has been carried out with the aim of improving the microstructure and hydrogen embrittlement resistance of UHSHSS. The effect of Nb-V alloying on the precipitation thermodynamics of precipitates has been investigated by Jmatpro software. Then, the distribution of precipitates and their influence on the microstructure have been explored by microstructural observation. Moreover, electrochemical hydrogen charging experiments and slow strain rate tests (SSRT) have been employed to evaluate the contribution of Nb and V alloying on the hydrogen embrittlement resistance of UHSHSS. The results show that the precipitates in Nb and V alloyed UHSHSS are almost complex carbides of (Nb, Ti, V) (C, N) at grain boundaries and within grains. The fine and diffuse precipitates refine the grain size, which reduces the average size of the primary austenite grains from 12.13 μm to 8.53 μm, and the number of small-angle grain boundaries is about 1.75 times that of traditional 22MnB5 steel. The hydrogen embrittlement susceptibility of UHSHSS is high, with hydrogen embrittlement indices of 50.12% and 69.57% for Nb and V alloyed UHSHSS and 22MnB5, respectively. The fracture morphology of the SSRT specimen with H-charging shows a quasi-cleavage feature with secondary cracks for 22MnB5, while the alloyed fracture mainly exhibits a mixture of quasi-cleavage and dimpled features characteristics, which indicates that the hydrogen embrittlement resistance has been significantly improved. The dispersed precipitates and refined microstructure resulting from the Nb and V alloying are the key factors improving the hydrogen embrittlement resistance.