Acrylamide-based polymers have been widely applied in drilling fluids due to their excellent water solubility, structural tunability, and adaptability to various fluid systems. However, under high-temperature downhole conditions, these polymers are prone to molecular chain degradation, conformational collapse, and reduced adsorption capacity, resulting in a significant decline in rheological control and filtration loss performance. These limitations severely restrict their application in high-temperature wells. Enhancing the structural stability and functional durability of polymers under elevated temperatures has become a critical challenge in the development of high-performance drilling fluid materials. Isoprenol polyoxyethylene ether (TPEG) has been demonstrated to improve the thermal resistance of acrylamide-based polymers. Nevertheless, incorporating TPEG into polymer chains contradicts the conventional design paradigm that seeks to eliminate thermally labile structures in high-temperature-resistant polymers. Therefore, elucidating the microscopic mechanisms by which TPEG modulates polymer chain evolution, conformational behavior, thermal degradation pathways, and adsorption characteristics at elevated temperatures is essential to understanding its synergistic effect. In this study, isoprenol polyoxyethylene ether (the most commonly used type with a molecular weight of 2400 was chosen, TPEG-2400) was introduced into a DMAA/AMPS acrylamide-based copolymer system and systematically compared with conventional DMAA/AMPS binary copolymers. The incorporation of TPEG-2400 significantly enhanced the thermal conformational stability and clay adsorption capacity of the polymer, enabling the drilling fluid to retain favorable rheological and filtration properties even after aging at 220 °C. The mechanism of action was elucidated by correlating changes in the physicochemical properties of the polymer with the analysis of its thermal degradation products. The highly flexible polyether structure was found to hinder interchain entanglement and coiling, while the strongly hydrophilic polyether segments formed a robust hydration layer, increasing electrostatic repulsion between clay particles. Moreover, the polyether chains may exhibit a “self-sacrificing” behavior under high-temperature conditions, preferentially decomposing to protect key functional groups such as amide moieties from thermal damage. This cooperative effect, from both conformational and thermodynamic perspectives, contributes to delaying polymer failure. It is concluded that the functional behavior of the segment structure plays a more significant role than its intrinsic thermal stability in enhancing the effective operating temperature of acrylamide-based polymers in drilling fluids. This counterintuitive yet strategically effective approach—introducing structurally specific but thermally less stable segments to achieve performance enhancement—offers a novel design perspective for future development of high-temperature-resistant polymer additives in drilling fluids