<p>Water under molecular-scale confinement is not simply a geometrically restricted form of bulk water, but can acquire distinct electronic, structural, and collective properties. However, how such an extremely confined state reshapes water’s intrinsic chemistry remains poorly understood. Here, using ab-initio calculations and enhanced-sampling machine-learning potential molecular dynamics, we show that extreme two-dimensional confinement activates water for proton generation. Monolayer-confined water exhibits a substantially lower free-energy barrier for forming separated H3O+ and OH− ions than bulk water, and this tendency is further enhanced by lateral compression and nuclear quantum fluctuations. This enhanced reactivity does not arise from a uniform weakening of all water molecules. Instead, confinement makes OH bond breaking selectively. The water molecule contains electronically distinct OH bonds, with weak in-plane bonds preferentially activated for proton release, while stronger dangling bonds remain relatively inactive. The surrounding hydrogen-bond network then provides disordered pathways for proton relocation, and the enhanced in-plane polarization stabilizes the charged products. Our results suggest that two-dimensional confined water can act as an active and superdielectric medium as indicated by recent experiments. Our findings reveal extreme confinement as a route to tune water-mediated chemistry, with implications for nanofluidics, geochemical pores, biological environments, and catalytic interfaces.</p>