The study investigates the thermal stability of Ti3C2Tx MXene flakes in air, focusing on the role of confined water in their oxidation. MXenes, known for their tunable surface chemistry and metallic conductivity, are widely used in various applications. However, their oxidation at high temperatures is a significant challenge. The research reveals that Ti3C2Tx monoflakes exhibit exceptional thermal stability up to 600 °C in air, while multiflakes readily oxidize at 300 °C. Density functional theory (DFT) calculations indicate that confined water between flakes has higher removal energy compared to surface water, leading to oxidation. Confined water can be fully removed by vacuum annealing at 600 °C, significantly improving the thermal stability of multiflake films. This finding provides insights into the kinetics of confined water and its role in MXene oxidation, enabling the use of stable monoflake MXenes in high-temperature applications. The study also highlights the importance of proper vacuum annealing conditions for enhancing the stability of multiflake MXene films.The study investigates the thermal stability of Ti3C2Tx MXene flakes in air, focusing on the role of confined water in their oxidation. MXenes, known for their tunable surface chemistry and metallic conductivity, are widely used in various applications. However, their oxidation at high temperatures is a significant challenge. The research reveals that Ti3C2Tx monoflakes exhibit exceptional thermal stability up to 600 °C in air, while multiflakes readily oxidize at 300 °C. Density functional theory (DFT) calculations indicate that confined water between flakes has higher removal energy compared to surface water, leading to oxidation. Confined water can be fully removed by vacuum annealing at 600 °C, significantly improving the thermal stability of multiflake films. This finding provides insights into the kinetics of confined water and its role in MXene oxidation, enabling the use of stable monoflake MXenes in high-temperature applications. The study also highlights the importance of proper vacuum annealing conditions for enhancing the stability of multiflake MXene films.