<p>The development of advanced titanium alloys capable of operating above 600 °C remains a critical challenge for aerospace propulsion systems, where conventional Ti alloys suffer from insufficient high-temperature strength and microstructural instability. Here, we propose a computationally driven design strategy for titanium-based medium-entropy alloys (MEAs) that integrates thermodynamic phase prediction with mechanistically informed strength modeling, enabling systematic exploration of the Ti-Nb-Al-Cr quaternary system. The optimized Ti₇₀Nb₁₀Al₁₅Cr₅ MEA exhibits exceptional performance metrics: 18% room-temperature ductility (as-cast), a yield strength of 520.7 MPa at 650 °C (post-aging), and an ultralow density of 4.76 g/cm³ (45% lighter than Inconel 718). Microstructural characterization reveals a metastable single-phase BCC structure in the as-cast state, which transforms into a BCC/Ti₃Al dual-phase system upon aging, with temperature-dependent precipitate morphology and phase stability. The alloy demonstrates superior high-temperature strength retention up to 900 °C (&gt;80 MPa yield strength), outperforming commercial titanium alloys (e.g., Ti-1100, TG6) and bridging the performance gap between conventional Ti alloys and nickel-based superalloys. This work establishes a multi-criteria design paradigm for entropy-engineered alloys, offering a viable pathway to lightweight, high-temperature structural materials for next-generation aerospace applications.</p>