This study investigates the molecular mechanisms underlying drought resistance heterosis (DRH) in rice, specifically using the water-saving and drought-resistant rice hybrid Hanyou73 (HY73) and its parental lines Hanhui3 (HH3) and Huhan7B (HH7B). Given the significant impact of drought stress on global food security, improving crop drought resistance is paramount. Our research focused on the proteome-level responses in flag leaves during the critical grain-filling stage under both well-watered (WW) and drought-stressed (DS) conditions. Our primary aim was to unravel the complex proteome dynamics and identify key regulatory pathways that contribute to DRH. Through comprehensive DIA-MS-based proteomic analysis, we sought to pinpoint proteins differentially regulated in response to drought and those exhibiting non-additive effects (NAE) in the hybrid. Specifically, we clarified how proteome remodeling supports enhanced carbon metabolism, identified critical protein post-translational modifications (PTMs) such as lysine acetylation (Kac), and uncovered key metabolic hubs like the "MOS-AcCoA-FA/PR" pathway in conferring HY73's drought resistance advantage. This rich dataset serves as a valuable resource for understanding the proteomic underpinnings of drought adaptation and heterosis in rice, offering promising targets for future crop improvement strategies.