GH4099 alloy, a typical precipitation-strengthened nickel-based superalloy, exhibits exceptional structural stability at temperatures up to 900 oC without forming topologically close-packed (TCP) phases. This superior high-temperature performance positions it as an ideal material for critical hot-end components in aero-engines, where its service reliability relies on synergistic strengthening mechanisms. Hot isostatic pressing (HIP), a powder metallurgy (PM) technique, enables near-net-shape fabrication of components with tailored microstructures and cost efficiency. However, inhomogeneous cooling rates in large-scale HIP-processed parts may compromise microstructure uniformity, necessitating systematic exploration of cooling rate effects on PM GH4099 alloy. In this study, GH4099 pre-alloyed powder was prepared via plasma rotating electrode process (PREP), and fully dense billets were consolidated by HIP at 1230 oC /150 MPa/4 h. The dual-stage heat treatment (solution: 1175 oC /1 h; aging: 850 oC /5 h) with varied cooling rates (argon quenching >50 oC /min, furnace cooling≈8 oC/min, controlled cooling 5 oC /min) was applied to investigate their regulatory roles in multi-scale microstructure evolution and high-temperature mechanical properties. Orthogonal experiments demonstrated that controlled cooling at 5 oC /min during both solution and aging stages (S3-A3) yielded optimal tensile strength (404.3 MPa) and elongation (34.7%) at 900 oC, with a 79.3% enhancement in high-temperature plasticity compared to gas-quenched solution combined with slow-cooled aging (S1-A3). Microstructural analysis revealed that slow cooling modulated γ' precipitation kinetics, suppressed continuous brittle phase (e.g., TiC) distribution at prior particle boundaries (PPBs), and promoted annealing twin formation (59.3% area fraction). These microstructural advantages synergistically enhanced grain boundary compatibility and inhibited crack propagation. This work elucidates the coupling mechanisms among cooling rate, γ' phase behavior, grain boundary characteristics, and PPBs evolution. The proposed HIP-graded cooling strategy offers a theoretical and technical foundation for microstructure-property integrated design of aerospace components under extreme thermal-mechanical conditions.