MXenes are layered two-dimensional materials with exciting properties useful to a wide range of energy applications. They are derived from ceramics (MAX phases) by leaching, and their properties reflect their resulting complex compositions which include intercalating cations and anions and water. Their thermodynamic stability is likely linked to these functional groups but has not yet been addressed by quantitative experimental measurements. We report enthalpies of formation from the elements at 25 °C measured using high temperature oxide melt solution calorimetry for a layered Ti–Al–C MAX phase, and the corresponding Ti–C based MXene. The thermodynamic stability of the Ti3C2Tx MXene (Tx stands for anionic surface moieties, and intercalated cations) was assessed by calculating the enthalpy of reaction of the MAX phase (ideal composition Ti3AlC2) to form MXene. The very exothermic enthalpy of reaction confirms the stability of MXene in an aqueous environment. The surface terminations (O, OH, and F) and cations (Li) chemisorbed on the surface and intercalated in the interlayers play a major role in the thermodynamic stabilization of MXene. These findings help in understanding and potentially improving properties and performance by characterizing the energetics of species binding to MXene surfaces during synthesis and in energy storage, water desalination, and other applications.