Abstract: We investigated the critical influence of in-situ nanoparticles on the mechanical properties and hydrogen embrittlement (HE) of high-strength steel. The results reveal that the mechanical strength and elongation of quenched and tempered steel (919 MPa yield strength, 17.11% elongation) are greater than those of hot-rolled steel (690 MPa yield strength, 16.81% elongation) due to the strengthening effect of in-situ Ti₃O₅–Nb(C,N) nanoparticles. In addition, the HE susceptibility is substantially mitigated to 55.52%, approximately 30% lower than that of steels without in-situ nanoparticles (84.04%), which we attribute to the heterogeneous nucleation of the Ti₃O₅ nanoparticles increasing the density of the carbides. Compared with hard TiN inclusions, the spherical and soft Al₂O₃–MnS core–shell inclusions that nucleate on in-situ Al₂O₃ particles could also suppress HE. In-situ nanoparticles generated by the regional trace-element supply have strong potential for the development of high-strength and hydrogen-resistant steels.