Ring-opening polymerization (ROP) enthalpy ΔHROP is an important thermodynamic property controlling the polymerization of cyclic monomers. While ΔHROP can be measured, computing ΔHROP for realistic polymer systems with an error of ≃5-10 kJ/mol is critical for designing new monomer systems for depolymerizable polymers. We have developed a first-principles computational scheme in which multiple challenges in computing ΔHROP are resolved definitively including extensive exploration of conformational states and adequately addressing finite size effects. This scheme is validated on a diverse benchmark set of 42 ROP polymers for which reliable experimental values of ΔHROP are available. For this set, the ΔHROP root-mean-square error is ≃7 kJ/mol, about 3-times smaller than conventional approaches. This development opens up new pathways to build up a high-quality database of ΔHROP for downstream predictive machine-learning models and ultimately to accelerate the design of depolymerizable polymers with desired properties.