The morphology and size of second phase greatly influence the strengthening effect on oxidation dispersion strengthened Mo alloys. In this work, a novel nanostructuring strategy is adopted to modify the second phase of Y₂O₃, and the corresponding effects of particle shape and size on mechanical properties of sintered Mo-Y₂O₃ alloys were investigated. It is found that spherical particles with sizes below 200 nm are preferred due to the dominant intragranular distribution of second phases associated with better strengthening effect originating from dislocation pinning. With smaller particle size of Y₂O₃ nanospheres (105 nm), the tensile strength of corresponding Mo alloy is enhanced by about 43.8%, much higher than that (8.3%) reinforced by second phase nanospheres with larger particle size (322 nm). Meanwhile, with similar particle size (around 100 nm), the spherical shape exhibits better strengthening effect than the one reinforced by one-dimensional rod-like second phase.