High entropy alloy (HEA) engineering offers a powerful route to stabilize semiconductor quantum dots (QDots) under harsh thermal and photonic environments. In this work, we develop a unified quantum mechanical and empirical framework to elucidate the thermal activation behavior of CdSe–HEA QDots. Quantum level modeling shows that multielement HEA interfaces introduce distributed electronic states, suppress surface traps, and enhance radiative exciton recombination by modifying the local potential landscape of the CdSe core. To quantify the resulting stability, we employ an Arrhenius based degradation formalism, treating photoluminescence (PL) decay as a first order thermally activated process. The HEA modifi ed QDots exhibit a significantly higher activation energy (0.90 eV) compared to bare CdSe (0.60 eV), leading to an exponential increase in emissive lifetime. Empirical predictions reveal a 10³–10⁴ fold lifetime enhancement across 350–500 K and sustained PL retention (S > 0.95) up to ~480 K, extending the operational temperature window by nearly 100 K. Composite analyses including Arrhenius plots, stability maps, and lifetime enhancement curves demonstrate that configurational entropy stabilization in the HEA shell effectively suppresses nonradiative pathways and thermal degradation. These results establish CdSe–HEA QDots as robust, entropy stabilized nanomaterials with strong potential for high temperature optoelectronic, photocatalytic, and energy conversion applications.