<p>High-speed milling of nickel-based super-alloys, particularly Inconel 718, is challenging due to their low thermal conductivity, high-temperature strength, and severe tool wear, affecting surface integrity and material performance. In addition, serrated chip formation during the machining of these alloys added more impact on the surface characteristics and microstructural changes. While many studies have focused on Inconel 718 machinability in turning, few have explored the impact of machining variables on microstructure and chip formation during high-speed milling. This study investigates the microstructure and serrated chip formation in high-speed milling of Inconel 718, aiming to optimize machining parameters for better surface integrity and material performance. First, milling experiments with various cutting parameters were conducted to determine their impact on cutting forces, temperature, and microstructural changes. Secondly, a simplified 2D milling model using a numerical-based, Johnson–Cook (J-C) constitutive material model was proposed to comprehend the serrated chip development during the milling of Inconel 718 alloy. Thirdly, progressive characterization approaches such as scanning electron microscope (SEM) and electron back-scattered diffraction (EBSD) were applied to consider the microstructural changes and phase composition analysis based on cutting forces and cutting temperature. Finally, the nano-indentation system assessed the underneath machined surface hardness. The conclusions demonstrate a localized plastic deformation on the machined surface and subsurface. Furthermore, the experimental results validated the proposed 2D milling model, showing a strong correlation with the simulation, particularly in chip morphology. This research provides insights into serrated chip formation during high-speed milling of Inconel 718 alloy, aiding in surface integrity preservation and process optimization.</p>