To address the internal defects and low room-temperature ductility of cast Ti-24Al-15Nb-1Mo alloy, the effects of hot isostatic pressing (HIP) process parameters (temperature, pressure, and holding time) on its microstructure and room-temperature ductility are investigated. An orthogonal experimental design is adopted. The alloy specimens melted and cast in a vacuum consumable skull furnace are subjected to HIP treatment with different process parameters. X-ray transmission is used to characterize the closure of porosity. Combined with scanning electron microscopy and X-ray diffraction, the phase constitution and distribution are analyzed, and room-temperature tensile property tests are carried out. The results show that under HIP treatments with different process parameters, casting defects including porosity and shrinkage cavities below ϕ1-4 mm in the as-cast Ti-24Al-15Nb-1Mo alloy are completely eliminated. Range analysis indicates that temperature exerts the most significant effect on the room-temperature ductility of the alloy, followed by pressure, while holding time has the weakest effect. After HIP treatment at 1000 ℃ under 130 MPa for 2 h, the room-temperature tensile strength of the alloy increases to 887 MPa, which is 15% higher than that of the as-cast alloy; the elongation rises to 2.95%, 4.9 times that of the as-cast alloy. Therefore, HIP markedly improves the room-temperature ductility of the alloy via defect healing and synergistic microstructure optimization.