The commercialization of high-energy batteries with lithium-rich cathode materials exhibiting combined cationic/anionic redox processes awaits the elimination of certain practical bottlenecks. Among these, large voltage hysteresis remains the most obscure from a fundamental thermochemical perspective. Here, we study this issue by directly measuring, via isothermal calorimetry, the heat generated by Li/Li2Ru0.75Sn0.25O3 (Li/LRSO) cells during various cycling conditions, with LRSO being a ‘model’ Li-rich layered cathode. We show how this heat thermodynamically relates to the lost electrical work that is crucial for practical applications. We further reveal that anionic redox on charging and discharging adopts different metastable paths having non-identical enthalpy potentials, such that the overall Li content no longer remains the unique reaction coordinate, unlike in fully path-reversible cationic redox. We elucidate how quasi-static voltage hysteresis is related to heat dissipated due to non-equilibrium entropy production. Overall, this study establishes the great benefits of isothermal calorimetry for enabling energy-efficient electrode materials in next-generation batteries.