In investment casting of titanium alloys, the interface reaction between ceramic cores and titanium alloy is a challenge to be solved, and Y2O3 with high-temperature chemically inert becomes a reliable candidate for the ceramic cores. In this work, high-purity Y2O3 ceramic cores were manufactured employing high-purity Y2O3 powder without any mineralizers, and the microstructure and properties were optimized by controlled particle gradation and solid loading. As the ratio of coarse to fine Y2O3 powders was 7:3, the fine powders filled the skeleton structure formed by coarse particles, achieving high strength along with adequate porosity. With solid loading of 88 wt%, the Y2O3 ceramic cores with superior performance were achieved, whose apparent porosity was 32.57 %, surface roughness was 1.71 mu m, high-temperature creep deformation was 0.268 mm, flexural strengths were 20.70 MPa at room temperature and 18.13 MPa at high temperature. After centrifugal casting of TC4 titanium alloy based on the Y2O3 ceramic cores, no interface reaction was detected between the titanium alloy and ceramic cores, and element deviation between interface and the interior of titanium alloy was invisible, which both confirmed the superior chemical compatibility of Y2O3 ceramic cores in investment casting of titanium alloys. This work inspires new guidance to Y2O3 ceramic cores for investment casting of titanium alloys.