<p>Molybdenum (Mo) is a promising structural material for high-temperature applications; however, its strength, particularly its plasticity and toughness, requires further improvement to meet the demands of advanced applications. To enhance strength and plasticity, an oxide dispersion-strengthened (ODS) Mo-Re alloy was developed by combining Y₂O₃ dispersion strengthening with rhenium (Re) alloying. The ODS-Mo-14Re alloy containing 0.5 wt% Y₂O₃ was fabricated using high-energy ball milling, hydrogen sintering, and thermomechanical processing. Experimental results show that the ODS-Mo-14Re alloy containing 0.5 wt% Y₂O₃ exhibits a 14% increase in tensile strength and a 41% increase in elongation at room temperature, compared to the Mo-14Re alloy, achieving a well-balanced improvement in both strength and ductility within a refractory metal system. The strength enhancement primarily stems from the dispersion-strengthening effect of Y₂O₃ nanoparticles (~ 74&#xa0;nm), which effectively pin dislocations. The improved ductility results from the synergistic contributions of several mechanisms: (1) the nanoparticles promote sub-grain refinement and structural stability, improving deformation compatibility; (2) Y–Re–O complex phases formed at the particle surfaces scavenge free oxygen and mitigate interfacial embrittlement; (3) first-principles calculations reveal that the Mo-Y₂O₃ interface exhibits inherently higher bonding strength than pure grain boundaries, thereby preventing microcrack initiation and propagation. The addition of Re further enhances interfacial cohesion to some extent. These findings demonstrate that the coordinated introduction of oxide particles and alloying elements can effectively overcome the conventional trade-off between strength and ductility in molybdenum alloys, providing novel strategies and theoretical foundations for the development of high-performance refractory structural materials.</p> Graphical Abstract <p></p>