Herein, the composition of ODS MA754 alloy was recomposed by adding alloying elements such as W, Mo, Zr, and optimizing the content of Y₂O₃, then, two novel types of alloy powders with the same composition but different oxygen contents of low (M1) and high (MA4) were respectively prepared via melting-atomization method or mechanical alloying method. Next, two novel nickel-based ODS alloys, namely M1- and MA4-alloy, were prepared with these two powders as raw material, respectively, via a “hot isostatic pressing + forging + heat treatment” process. Meanwhile, the influence of the powdering techniques on the microstructure and tensile properties of the acquired alloys at different processing stages was assessed. The results showed that the MA4 alloy presents a microstructure with much uniformly dispersed nanoscale oxides like Y-Zr-Al-O and Y-Al-O compared to that of the M1 alloy. The density of the HIPed MA4 alloy is also superior to that of the M1 alloy. After forging, the second-phase particles in the MA4 alloy are finer and more evenly distributed, their role in pinning grain boundaries and inhibiting grain growth is strengthened. Solid solution treatment and solid solution + aging treatment slightly reduce the strength of the MA4 alloy but significantly increase its elongation after fracture. Compared to the M1 alloy, the strength of the MA4 alloy at all processing stages is superior. Moreover, as the solution treatment and solution treatment + aging processes are implemented, the increment in tensile and yield strength of the former is higher than the latter. The MA4 alloys acquired at the forged state, solution-treated state, and the solution + aging state, their tensile strength is 13.7%, 13.1%, and 19.9% higher, while the yield strength is 24.1%, 30.8%, and 59.0% higher, respectively, rather than those of M1 alloys. The post-fracture elongation of the MA4 alloy is lower than that of the M1 alloy to a certain extent. The MA4 alloy obtained by the solution + aging treatment stage, their post-fracture elongation was reduced to only 12.9% of the M1 alloy. Additionally, the hardness of the MA4 alloy is generally higher than that of the M1 alloy. After aging treatment, the MA4 alloy exhibits good microstructural uniformity, whereas the M1 alloy experiences abnormal grain growth, leading to microstructural inhomogeneity, which accounts for the variation in its mechanical properties. It follows that mechanical alloying is more suitable for preparing nickel-based ODS alloys.