Entropy production in quasi-isentropic compression (QIC) is critically important for understanding the properties of materials under extreme conditions. However, the origin and accurate quantification of entropy in this situation remain long-standing challenges. In this work, a framework is established for the quantification of entropy production and partition, and their relation to microstructural change in QIC. Cu₅₀Zr₅₀ is taken as a model material, and its compression is simulated by molecular dynamics. On the basis of atomistic simulation-informed physical properties and free energy, the thermodynamic path is recovered, and the entropy production and its relation to microstructural change are successfully quantified by the proposed framework. Contrary to intuition, entropy production during QIC of metallic glasses is relatively insensitive to the strain rate $\dot{\gamma }$ when $\dot{\gamma }$ ranges from 7.5 × 10⁸ to 2 × 10⁹/s, which are values reachable in QIC experiments, with a magnitude of the order of 10^-2k_B/atom per GPa. However, when $\dot{\gamma }$ is extremely high ($>2\times 10^9/\text{s}$), a notable increase in entropy production rate with $\dot{\gamma }$ is observed. The Taylor–Quinney factor is found to vary with strain but not with strain rate in the simulated regime. It is demonstrated that entropy production is dominated by the configurational part, compared with the vibrational part. In the rate-insensitive regime, the increase in configurational entropy exhibits a linear relation to the Shannon-entropic quantification of microstructural change, and a stretched exponential relation to the Taylor–Quinney factor. The quantification of entropy is expected to provide thermodynamic insights into the fundamental relation between microstructure evolution and plastic dissipation.