The results of a thermochemical study of the standard molar enthalpy of combustion of 2-adamantanone in the crystalline phase state by isoperibol combustion calorimetry are presented. Two different approaches of combustion-calorimetry data processing (one from 1956 traditionally used in the field and another from 2021 updated with respect to equations and reference values) were compared and shown to give nearly indistinguishable results for 2-adamantanone (composed of only C, H, O elements). The results allowed resolving the observed inconsistency in the literature values of the enthalpy of formation of 2-adamantanone in the crystalline phase state published to date. The experimental standard enthalpy of formation for crystal was combined with the enthalpy of sublimation available in the literature to give the enthalpy of formation for gas, which is in excellent agreement with the gas-phase enthalpy of formation computed according to one of the most reliable quantum-chemical protocols. The enthalpy effect of the substitution of a methylene fragment with a carbonyl group was analyzed in a series of linear, branched, and cyclic alkanes. The evaluated effect indirectly confirms the absence of any measurable strain in 2-adamantanone in comparison to the parent molecule of adamantane.