Coherent γ'-phase precipitation strengthened heat-resistant Cu-based alloys exhibit promising application in the field of high-temperature. In the work, to further improve the comprehensive performance of the alloys, the elements Cr, Zr, Zn and Ti are introduced into the model alloy (Cu83.33Ni12.50Al4.17 at.%). The existence state of the adding elements and their influence on comprehensive properties, including the in-situ high-temperature hardness, tensile properties and stability, etc., was unveiled. Furthermore, the Cu83.33Ni11.11Al2.78Cr1.04Ti1.04Zr0.35Zn0.35 alloy with excellent comprehensive properties was designed and prepared, exhibiting a high-temperature tensile strength of 370 MPa and an elongation of 3.7 % and high temperature stability of up to 400 h at 873 K. The reasons for the improvement of comprehensive properties can be attributed to the following aspects: (1) The adding elements not only inhibit discontinuous precipitation but also refined the size of the γ' phase and improved its thermal stability; (2) Cr and Zr inhibit the precipitation of deleterious D024-Ni3Ti phase caused by Ti; (3) The BCC-Cr (precipitation strengthening phase) and Ni5Zr phases (grain boundary strengthening phase) are introduced. This study successfully demonstrates the advantages of addition of multiple-elements through regulating their interaction, thereby establishing a robust foundation for designing heat-resistant Cu-based alloys in future investigations.